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Sample records for stroke motor neurons

  1. Motor Neurons

    DEFF Research Database (Denmark)

    Hounsgaard, Jorn

    2017-01-01

    Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... properties of this facility in the path from synaptic sites to the motor axon is reviewed with emphasis on voltage sensitive ion channels and regulatory metabotropic transmitter pathways. The catalog of the intrinsic response properties, their underlying mechanisms, and regulation obtained from motoneurons...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

  2. [The importance of neuronal networks for motor rehabilitation after a stroke].

    Science.gov (United States)

    Hummel, F C

    2017-08-01

    Every year in Europe 1.5 million patients suffer a new stroke. Despite the further developments in acute therapy with nationwide stroke units, thrombolysis, thrombectomy and post-acute neurorehabilitation, only a small proportion of patients recover to a satisfactory degree allowing them to return to their normal social and professional life. This makes stroke the main cause of long-term disability with a corresponding impact on patient lives, socioeconomics and the healthcare system. Thus, the concepts of neurorehabilitation have to be extended to enhance the effects of rehabilitative treatment strategies. To achieve this, an understanding of the prediction of the course of recovery, the mechanisms underlying functional recovery and factors influencing recovery have to be enhanced for the development towards patient-tailored precision medicine approaches. A central point towards this is the understanding of stroke as a disease, which not only influences the damaged area but also the associated network. This is crucial for the understanding of the stroke-induced deficits, for prediction of recovery and options for interventional treatment strategies, which can target different areas in this network (e.g. primary motor cortex and secondary motor regions) based on individual factors of the patient. The present article discusses the importance of network alterations for motor neurorehabilitation after a stroke and which novel options, concepts and consequences could arise from this for neurorehabilitation.

  3. Neurons other than motor neurons in motor neuron disease.

    Science.gov (United States)

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  4. The effect of Bobath approach on the excitability of the spinal alpha motor neurones in stroke patients with muscle spasticity.

    Science.gov (United States)

    Ansari, N N; Naghdi, S

    2007-01-01

    A clinical study was performed to evaluate the efficacy of the Bobath approach on the excitability of the spinal alpha motor neurones in patients with poststroke spasticity. Ten subjects ranging in age from 37 through 76 years (average 60 years) with ankle plantarflexor spasticity secondary to a stroke were recruited and completed the trial. They had physiotherapy according to Bobath concept for ten treatment sessions, three days per week. Two repeated measures, one before and another after treatment, were taken to quantify clinical efficacy. The effect of this type of therapy on the excitability of alpha motor neurones (aMN) was assessed by measuring the latency of the Hoffmann reflex (H-reflex) and the Hmax/Mmax ratio. The original Ashworth scale and ankle range of motion were also measured. The mean HmaxlMmax ratio on the affected side at baseline was high in the study patients. However, there were no statistically significant differences in the HmaxlMmax ratio or in the H-reflex latency between the baseline values and those recorded after therapy intervention. Before treatment, the HmaxlMmax ratio was significantly higher in the affected side than in the unaffected side. However, it was similar at both sides after treatment. Following treatment, the significant reduction in spasticity was clinically detected as measured with the original Ashworth scale. The ankle joint active and passive range of motion was significantly increased. In conclusion, Bobath therapy had a statistically significant effect on the excitability of the aMN in the affected side compared to the unaffected side in stroke patients with muscle spasticity.

  5. The relation between Ashworth scale scores and the excitability of the alpha motor neurones in patients with post-stroke muscle spasticity.

    Science.gov (United States)

    Bakheit, A M O; Maynard, V A; Curnow, J; Hudson, N; Kodapala, S

    2003-05-01

    The modified Ashworth scale (MAS) is the most widely used method for assessing muscle spasticity in clinical practice and research. However, the validity of this scale has been challenged. To compare the MAS with objective neurophysiological tests of spasticity. The MAS was recorded in patients with post-stroke lower limb muscle spasticity and correlated with the excitability of the alpha motor neurones. The latter was evaluated by measuring the latency of the Hoffmann reflex (H reflex) and the ratio of the amplitude of the maximum H reflex (H(max)) to that of the compound action motor potential of the soleus muscle (M(max)). Data on 24 randomly recruited patients were analysed. Patients were divided into two groups according to their MAS score: 14 had a MAS score of 1 (group A) and 10 scored 2 (group B). The two groups were comparable with respect to age and sex, but in group A there was a longer period since the stroke. The H reflex latency was reduced and the H(max):M(max) ratio was increased in both groups. The H(max):M(max) ratio values were higher for group B but the differences were not statistically significant. There is a relation between the MAS scores and alpha motor neurone excitability, although it is not linear. This suggests that the MAS measures muscle hypertonia rather than spasticity.

  6. Motor neuron disease in blacks

    African Journals Online (AJOL)

    1989-08-19

    Aug 19, 1989 ... A series of 86 black, Indian and white patients with motor neuron disease were analysed retrospectively. Although the material does not allow statistically valid conclusions, there are sufficient cases among blacks to allow two prima facie observations in this population group: (~ motor neuron disease.

  7. Motor neuron disease in blacks

    African Journals Online (AJOL)

    1989-08-19

    Aug 19, 1989 ... We reported earlier that motor neuron disease occurs more commonly among blacks than Parkinson's disease, which is relatively rare in this race group.! The hypothesis that these conditions, and other neuronal abiotrophies, are the result of previous subclinical neuronal insult and subsequent age-related.

  8. Lower motor neuron findings after upper motor neuron injury: Insights from postoperative supplementary motor area syndrome

    Directory of Open Access Journals (Sweden)

    Jeffrey E Florman

    2013-03-01

    Full Text Available Hypertonia and hypereflexia are classically described responses to upper motor neuron injury. However, acute hypotonia and areflexia with motor deficit are hallmark findings after many central nervous system insults such as acute stroke and spinal shock. Historic theories to explain these contradictory findings have implicated a number of potential mechanisms mostly relying on the loss of descending corticospinal input as the underlying etiology. Unfortunately, these simple descriptions consistently fail to adequately explain the pathophysiology and connectivity leading to acute hyporeflexia and delayed hypereflexia that result from such insult. This article highlights the common observation of acute hyporeflexia after central nervous system insults and explores the underlying anatomy and physiology. Further, evidence for the underlying connectivity is presented and implicates the dominant role of supraspinal inhibitory influence originating in the supplementary motor area descending through the corticospinal tracts. Unlike traditional explanations, this theory more adequately explains the findings of postoperative supplementary motor area syndrome in which hyporeflexive motor deficit is observed acutely in the face of intact primary motor cortex connections to the spinal cord. Further, the proposed connectivity can be generalized to help explain other insults including stroke, atonic seizures, and spinal shock.

  9. Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection

    Science.gov (United States)

    Adkins, DeAnna L.

    2015-01-01

    Stroke instigates regenerative responses that reorganize connectivity patterns among surviving neurons. The new connectivity patterns can be suboptimal for behavioral function. This review summarizes current knowledge on post-stroke motor system reorganization and emerging strategies for shaping it with manipulations of behavior and cortical activity to improve functional outcome. PMID:26328881

  10. The mirror neuron system in post-stroke rehabilitation

    Science.gov (United States)

    2013-01-01

    Different treatments for stroke patients have been proposed; among them the mirror therapy and motion imagery lead to functional recovery by providing a cortical reorganization. Up today the basic concepts of the current literature on mirror neurons and the major findings regarding the use of mirror therapy and motor imagery as potential tools to promote reorganization and functional recovery in post-stroke patients. Bibliographic research was conducted based on publications over the past thirteen years written in English in the databases Scielo, Pubmed/MEDLINE, ISI Web of Knowledge. The studies showed how the interaction among vision, proprioception and motor commands promotes the recruitment of mirror neurons, thus providing cortical reorganization and functional recovery of post-stroke patients. We conclude that the experimental advances on Mirror Neurons will bring new rational therapeutic approaches to post-stroke rehabilitation. PMID:24134862

  11. The spectrum of lower motor neuron syndromes

    NARCIS (Netherlands)

    van den Berg-Vos, R. M.; van den Berg, L. H.; Visser, J.; de Visser, M.; Franssen, H.; Wokke, J. H. J.

    2003-01-01

    This review discusses the most important lower motor neuron syndromes. This relatively rare group of syndromes has not been well described clinically. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) are primarily affected or motor axons and

  12. Cognition and behavior in motor neuron disease

    NARCIS (Netherlands)

    Raaphorst, J.

    2015-01-01

    Motor neuron disease (MND) is a devastating neurodegenerative disorder characterized by progressive motor neuron loss, leading to weakness of the muscles of arms and legs, bulbar and respiratory muscles. Depending on the involvement of the lower and the upper motor neuron, amyotrophic lateral

  13. Differentiating lower motor neuron syndromes.

    Science.gov (United States)

    Garg, Nidhi; Park, Susanna B; Vucic, Steve; Yiannikas, Con; Spies, Judy; Howells, James; Huynh, William; Matamala, José M; Krishnan, Arun V; Pollard, John D; Cornblath, David R; Reilly, Mary M; Kiernan, Matthew C

    2017-06-01

    Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. Interactive visuo-motor therapy system for stroke rehabilitation.

    Science.gov (United States)

    Eng, Kynan; Siekierka, Ewa; Pyk, Pawel; Chevrier, Edith; Hauser, Yves; Cameirao, Monica; Holper, Lisa; Hägni, Karin; Zimmerli, Lukas; Duff, Armin; Schuster, Corina; Bassetti, Claudio; Verschure, Paul; Kiper, Daniel

    2007-09-01

    We present a virtual reality (VR)-based motor neurorehabilitation system for stroke patients with upper limb paresis. It is based on two hypotheses: (1) observed actions correlated with self-generated or intended actions engage cortical motor observation, planning and execution areas ("mirror neurons"); (2) activation in damaged parts of motor cortex can be enhanced by viewing mirrored movements of non-paretic limbs. We postulate that our approach, applied during the acute post-stroke phase, facilitates motor re-learning and improves functional recovery. The patient controls a first-person view of virtual arms in tasks varying from simple (hitting objects) to complex (grasping and moving objects). The therapist adjusts weighting factors in the non-paretic limb to move the paretic virtual limb, thereby stimulating the mirror neuron system and optimizing patient motivation through graded task success. We present the system's neuroscientific background, technical details and preliminary results.

  15. Motor neurons and the generation of spinal motor neurons diversity

    Directory of Open Access Journals (Sweden)

    Nicolas eStifani

    2014-10-01

    Full Text Available Motor neurons (MNs are neuronal cells located in the central nervous system (CNS controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal motor neurons (SpMNs that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate.Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate.This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies.

  16. Neuronal Cell Sheets of Cortical Motor Neuron Phenotype Derived from Human iPSCs.

    Science.gov (United States)

    Suzuki, Noboru; Arimitsu, Nagisa; Shimizu, Jun; Takai, Kenji; Hirotsu, Chieko; Ueda, Yuji; Wakisaka, Sueshige; Fujiwara, Naruyoshi; Suzuki, Tomoko

    2017-08-01

    Transplantation of stem cells that differentiate into more mature neural cells brings about functional improvement in preclinical studies of stroke. Previous transplant approaches in the diseased brain utilized injection of the cells in a cell suspension. In addition, neural stem cells were preferentially used for grafting. However, these cells had no specific relationship to the damaged tissue of stroke and brain injury patients. The injection of cells in a suspension destroyed the cell-cell interactions that are suggested to be important for promoting functional integrity of cortical motor neurons. In order to obtain suitable cell types for grafting in patients with stroke and brain damage, a protocol was modified for differentiating human induced pluripotent stem cells from cells phenotypically related to cortical motor neurons. Moreover, cell sheet technology was applied to neural cell transplantation, as maintaining the cell-cell communications is regarded important for the repair of host brain architecture. Accordingly, neuronal cell sheets that were positive Forebrain Embryonic Zinc Finger (Fez) family zinc finger 2 (FEZF2), COUP-TF-interacting protein 2, insulin-like growth factor-binding protein 4 (IGFBP4), cysteine-rich motor neuron 1 protein precursor (CRIM1), and forkhead box p2 (FOXP2) were developed. These markers are associated with cortical motoneurons that are appropriate for the transplant location in the lesions. The sheets allowed preservation of cell-cell interactions shown by synapsin1 staining after transplantation to damaged mouse brains. The sheet transplantation brought about partial structural restoration and the improvement of motor functions in hemiplegic mice. Collectively, the novel neuronal cell sheets were transplanted into damaged motor cortices; the cell sheets maintained cell-cell interactions and improved the motor functions in the hemiplegic model mice. The motoneuron cell sheets are possibly applicable for stroke patients and

  17. Sleep disordered breathing in motor neurone disease

    OpenAIRE

    D’Cruz, Rebecca F.; Murphy, Patrick B.; Kaltsakas, Georgios

    2018-01-01

    Motor neurone disease (MND) is a neurodegenerative disease defined by axonal loss and gliosis of upper and lower motor neurones in the motor cortex, lower brainstem nuclei and ventral horn of the spinal cord. MND is currently incurable and has a poor prognosis, with death typically occurring 3 to 5 years after disease onset. The disease is characterised by rapidly progressive weakness leading to paralysis, fasciculations, bulbar symptoms (including dysarthria and dysphagia) and respiratory co...

  18. Motor aging results from cerebellar neuron death.

    Science.gov (United States)

    Boisgontier, Matthieu P

    2015-03-01

    As we age, movements become slower and inconsistent and require more attention. These hallmarks of aging suggest a switch from predictive to reactive motor control. Here I examine evidence supporting the hypothesis that motor aging is primarily determined by the early death of neurons in the cerebellum, a critical structure for predictive motor control. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    Science.gov (United States)

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  20. A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

    Science.gov (United States)

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

    2014-01-01

    SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

  1. Motors and Adaptors : Transport Regulation within Neurons

    NARCIS (Netherlands)

    van Spronsen, C.S.A.M.|info:eu-repo/dai/nl/337616655

    2012-01-01

    Human thoughts and behavior are the outcome of communication between neurons in our brains. There is an entire world inside each of these neurons where transactions are established and meeting points are set. By using molecular motors to transport proteins and organelles along cytoskeletal tracks,

  2. Motor and premotor cortices in subcortical stroke: proton magnetic resonance spectroscopy measures and arm motor impairment.

    Science.gov (United States)

    Craciunas, Sorin C; Brooks, William M; Nudo, Randolph J; Popescu, Elena A; Choi, In-Young; Lee, Phil; Yeh, Hung-Wen; Savage, Cary R; Cirstea, Carmen M

    2013-06-01

    Although functional imaging and neurophysiological approaches reveal alterations in motor and premotor areas after stroke, insights into neurobiological events underlying these alterations are limited in human studies. We tested whether cerebral metabolites related to neuronal and glial compartments are altered in the hand representation in bilateral motor and premotor areas and correlated with distal and proximal arm motor impairment in hemiparetic persons. In 20 participants at >6 months postonset of a subcortical ischemic stroke and 16 age- and sex-matched healthy controls, the concentrations of N-acetylaspartate and myo-inositol were quantified by proton magnetic resonance spectroscopy. Regions of interest identified by functional magnetic resonance imaging included primary (M1), dorsal premotor (PMd), and supplementary (SMA) motor areas. Relationships between metabolite concentrations and distal (hand) and proximal (shoulder/elbow) motor impairment using Fugl-Meyer Upper Extremity (FMUE) subscores were explored. N-Acetylaspartate was lower in M1 (P = .04) and SMA (P = .004) and myo-inositol was higher in M1 (P = .003) and PMd (P = .03) in the injured (ipsilesional) hemisphere after stroke compared with the left hemisphere in controls. N-Acetylaspartate in ipsilesional M1 was positively correlated with hand FMUE subscores (P = .04). Significant positive correlations were also found between N-acetylaspartate in ipsilesional M1, PMd, and SMA and in contralesional M1 and shoulder/elbow FMUE subscores (P = .02, .01, .02, and .02, respectively). Our preliminary results demonstrated that proton magnetic resonance spectroscopy is a sensitive method to quantify relevant neuronal changes in spared motor cortex after stroke and consequently increase our knowledge of the factors leading from these changes to arm motor impairment.

  3. Heavy metals in locus ceruleus and motor neurons in motor neuron disease.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2013-12-12

    The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.

  4. Heavy metals in locus ceruleus and motor neurons in motor neuron disease

    Science.gov (United States)

    2013-01-01

    Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

  5. Biosensors for brain trauma and dual laser doppler flowmetry: enoxaparin simultaneously reduces stroke-induced dopamine and blood flow while enhancing serotonin and blood flow in motor neurons of brain, in vivo.

    Science.gov (United States)

    Broderick, Patricia A; Kolodny, Edwin H

    2011-01-01

    Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox(®)), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT's selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE(®) biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE(®) laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin

  6. Biosensors for Brain Trauma and Dual Laser Doppler Flowmetry: Enoxaparin Simultaneously Reduces Stroke-Induced Dopamine and Blood Flow while Enhancing Serotonin and Blood Flow in Motor Neurons of Brain, In Vivo

    Directory of Open Access Journals (Sweden)

    Edwin H. Kolodny

    2010-12-01

    Full Text Available Neuromolecular Imaging (NMI based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox®, an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT’s selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE® biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS. In the present studies, BRODERICK PROBE® laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent

  7. Motor Imagery Impairment in Postacute Stroke Patients

    Directory of Open Access Journals (Sweden)

    Niclas Braun

    2017-01-01

    Full Text Available Not much is known about how well stroke patients are able to perform motor imagery (MI and which MI abilities are preserved after stroke. We therefore applied three different MI tasks (one mental chronometry task, one mental rotation task, and one EEG-based neurofeedback task to a sample of postacute stroke patients (n=20 and age-matched healthy controls (n=20 for addressing the following questions: First, which of the MI tasks indicate impairment in stroke patients and are impairments restricted to the paretic side? Second, is there a relationship between MI impairment and sensory loss or paresis severity? And third, do the results of the different MI tasks converge? Significant differences between the stroke and control groups were found in all three MI tasks. However, only the mental chronometry task and EEG analysis revealed paresis side-specific effects. Moreover, sensitivity loss contributed to a performance drop in the mental rotation task. The findings indicate that although MI abilities may be impaired after stroke, most patients retain their ability for MI EEG-based neurofeedback. Interestingly, performance in the different MI measures did not strongly correlate, neither in stroke patients nor in healthy controls. We conclude that one MI measure is not sufficient to fully assess an individual’s MI abilities.

  8. Disorders of motor neurons manifested by hyperactivity.

    Science.gov (United States)

    Grapperon, A M; Attarian, S

    2017-05-01

    Neuronal and/or axonal hyperactivity and hyperexcitability is an important feature of motor neuron diseases. It results clinically in cramps and fasciculations. It is not specific to motor neuron diseases, and can occur in healthy subjects, as well as in various pathologies of the peripheral nervous system, including nerve hyperexcitability syndromes. Hyperexcitability plays an important and debated role in the pathophysiology of motor neuron diseases, especially in amyotrophic lateral sclerosis (ALS). The mechanisms causing hyperexcitability are not yet clearly identified. While most studies favor a distal axonal origin site of fasciculations, some of the fasciculations could be of cortical origin. The consequences of hyperexcitability are also discussed, whether it is rather protective or deleterious in the disease course. Fasciculations are depicted both clinically and using electromyogram, and more recently the interest of ultrasound has been highlighted. The importance of fasciculation potentials in the diagnosis of ALS led to changes in electrophysiological criteria at Awaji consensus conference. The contribution of these modifications to ALS diagnosis has been the subject of several studies. In clinical practice, it is necessary to distinguish fasciculations potentials of motor neuron disease from benign fasciculations. In most studies of fasciculation potentials in ALS, the presence of complex fasciculation potentials appears to be relevant for the diagnosis and the prognosis of the disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Plasticity and response to action observation: a longitudinal FMRI study of potential mirror neurons in patients with subacute stroke.

    Science.gov (United States)

    Brunner, Iris C; Skouen, Jan Sture; Ersland, Lars; Grüner, Renate

    2014-01-01

    Action observation has been suggested as a possible gateway to retraining arm motor function post stroke. However, it is unclear if the neuronal response to action observation is affected by stroke and if it changes during the course of recovery. To examine longitudinal changes in neuronal activity in a group of patients with subacute stroke when observing and executing a bimanual movement task. Eighteen patients were examined twice using 3-T functional magnetic resonance imaging; 1 to 2 weeks and 3 months post stroke symptom onset. Eighteen control participants were examined once. Image time series were analyzed (SPM8) and correlated with clinical motor function scores. During action observation and execution, an overlap of neuronal activation was observed in the superior and inferior parietal lobe, precentral gyrus, insula, and inferior temporal gyrus in both control participants and patients (P < .05; false discovery rate corrected). The neuronal response in the observation task increased from 1 to 2 weeks to 3 months after stroke. Most activated clusters were observed in the inferior temporal gyrus, the thalamus and movement-related areas, such as the premotor, supplementary and motor cortex (BA4, BA6). Increased activation of cerebellum and premotor area correlated with improved arm motor function. Most patients had regained full movement ability. Plastic changes in neurons responding to action observation and action execution occurred in accordance with clinical recovery. The involvement of motor areas when observing actions early and later after stroke may constitute a possible access to the motor system. © The Author(s) 2014.

  10. Suicide in patients with motor neuron disease

    DEFF Research Database (Denmark)

    Bak, Søren; Stenager, E N; Stenager, Egon

    1994-01-01

    The aim of the present study was to assess, through an epidemiological study, whether suicide risk is increased in patients with motor neuron disease (MND). The study involved 116 patients with MND. In the study period 92 patients died, 47 males and 45 females. No patients committed suicide...

  11. Interventions for motor apraxia following stroke.

    Science.gov (United States)

    West, C; Bowen, A; Hesketh, A; Vail, A

    2008-01-23

    Apraxia is a cognitive disorder that can occur after stroke. It prevents a person from carrying out a learned movement. Various interventions are used to treat apraxia but evidence of their benefit has been lacking. To determine which therapeutic interventions targeted at motor apraxia reduce disability. We searched the Cochrane Stroke Group Trials Register (last searched November 2006). In addition, we searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2006), MEDLINE (1966 to November 2007), EMBASE (1980 to November 2006), CINAHL (1982 to November 2006), PsycINFO (1974 to November 2006), the Research Index of the Occupational Therapy Journal (searched November 2006), REHABDATA (1956 to November 2006), the National Research Register (searched November 2006) and Current Controlled Trials Register (searched November 2006). We reviewed the reference lists of all articles that we identified as relevant. We made efforts to find both published and unpublished trials by writing to key authors and journals. Randomised controlled trials of therapeutic intervention for motor apraxia in stroke. One review author searched the titles, abstracts and keywords. Four review authors extracted data and analysed trial quality. We contacted investigators for further details of trials if necessary. Three trials including a total of 132 participants were included in the review. There was evidence of a small and short-lived therapeutic effect in the two studies that reported change in activities of daily living (102 participants) but this was not considered clinically significant and did not persist at the longer-term follow up. There is insufficient evidence to support or refute the effectiveness of specific therapeutic interventions for motor apraxia after stroke. Further research of higher quality is required. As we did not review whether patients with apraxia benefit from rehabilitation input in general, they

  12. Protective effect of parvalbumin on excitotoxic motor neuron death

    DEFF Research Database (Denmark)

    Van den Bosch, L.; Schwaller, B.; Vleminckx, V.

    2002-01-01

    Amyotrophic lateral sclerosis, ALS, AMPA receptor, calcium-binding proteins, calcium buffering, excitotoxity, kainic acid, motor neuron, parvalbumin......Amyotrophic lateral sclerosis, ALS, AMPA receptor, calcium-binding proteins, calcium buffering, excitotoxity, kainic acid, motor neuron, parvalbumin...

  13. Muscle and motor neuron ciliary neurotrophic factor receptor α together maintain adult motor neuron axons in vivo.

    Science.gov (United States)

    Lee, Nancy; Serbinski, Carolyn R; Braunlin, Makayla R; Rasch, Matthew S; Rydyznski, Carolyn E; MacLennan, A John

    2016-12-01

    The molecular mechanisms maintaining adult motor innervation are comparatively unexplored relative to those involved during development. In addition to the fundamental neuroscience question, this area has important clinical ramifications given that loss of neuromuscular contact is thought to underlie several adult onset human neuromuscular diseases including amyotrophic lateral sclerosis. Indirect evidence suggests that ciliary neurotrophic factor (CNTF) receptors may contribute to adult motor neuron axon maintenance. To directly address this in vivo, we used adult onset mouse genetic disruption techniques to deplete motor neuron and muscle CNTF receptor α (CNTFRα), the essential ligand binding subunit of the receptor, and incorporated reporters labelling affected motor neuron axons and terminals. The combined depletion of motor neuron and muscle CNTFRα produced a large loss of motor neuron terminals and retrograde labelling of motor neurons with FluoroGold indicated axon die-back well beyond muscle, together revealing an essential role for CNTFRα in adult motor axon maintenance. In contrast, selective depletion of motor neuron CNTFRα did not affect motor innervation. These data, along with our previous work indicating no effect of muscle specific CNTFRα depletion on motor innervation, suggest that motor neuron and muscle CNTFRα function in concert to maintain motor neuron axons. The data also raise the possibility of motor neuron and/or muscle CNTFRα as therapeutic targets for adult neuromuscular denervating diseases. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  14. The Neuronal Network Orchestration behind Motor Behaviors

    DEFF Research Database (Denmark)

    Petersen, Peter Christian

    studies. In the second study, we looked into the distribution of firing rates during different motor programs and the mechanisms that give rise to the distribution. We implanted high-density silicon probes in the spinal cord and recorded parallel single unit activity while inducing different scratch......, and it remains skewed in different behaviors. Our findings support that the neuronal activity, which is involved in motor behavior, is governed by synaptic fluctuations and as a result thereof is irregular. Similar lognormal- like distributions of firing rates have also been observed in other brain areas...

  15. Orofacial Apraxia in Motor Neuron Disease

    OpenAIRE

    Patrícia Pita Lobo; Susana Pinto; Luz Rocha; Sofia Reimão; Mamede de Carvalho

    2013-01-01

    Introduction: Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods: We report a patient with MND who presented with spastic dysarthria and asymme...

  16. Spectroscopic biomarkers of motor cortex developmental plasticity in hemiparetic children after perinatal stroke.

    Science.gov (United States)

    Carlson, Helen L; MacMaster, Frank P; Harris, Ashley D; Kirton, Adam

    2017-03-01

    Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE = 30 ms, voxel = 4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration = 10.8 ± 1.9 vs. 12.0 ± 1.2, P children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy. Hum Brain Mapp 38:1574-1587, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. The frontotemporal dementia-motor neuron disease continuum.

    Science.gov (United States)

    Burrell, James R; Halliday, Glenda M; Kril, Jillian J; Ittner, Lars M; Götz, Jürgen; Kiernan, Matthew C; Hodges, John R

    2016-08-27

    Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron.

    Science.gov (United States)

    Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

    2016-01-01

    Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.

  19. Evaluation of Motor Recovery in Adult Patients with Hemiplegic stroke

    African Journals Online (AJOL)

    Background: Assessment of treatment efficacy through outcomes evaluation is an established practice in stroke rehabilitation. The evaluation of motor recovery is a cornerstone of the assessment of patients with stroke; and an integral component of stroke rehabilitation. Objective: The purpose of this study was to evaluate ...

  20. Action observation as a tool for neurorehabilitation to moderate motor deficits and aphasia following stroke

    Science.gov (United States)

    Ertelt, Denis; Binkofski, Ferdinand

    2012-01-01

    The mirror neuron system consists of a set of brain areas capable of matching action observation with action execution. One core feature of the mirror neuron system is the activation of motor areas by action observation alone. This unique capacity of the mirror neuron system to match action perception and action execution stimulated the idea that mirror neuron system plays a crucial role in the understanding of the content of observed actions and may participate in procedural learning. These features bear a high potential for neurorehabilitation of motor deficits and of aphasia following stroke. Since the first articles exploring this principle were published, a growing number of follow-up studies have been conducted in the last decade. Though, the combination of action observation with practice of the observed actions seems to constitute the most powerful approach. In the present review, we present the existing studies analyzing the effects of this neurorehabilitative approach in clinical settings especially in the rehabilitation of stroke associated motor deficits and give a perspective on the ongoing trials by our research group. The data obtained up to date showed significant positive effect of action observation on recovery of motor functions of the upper limbs even in the chronic state after stroke, indicating that our approach might become a new standardized add-on feature of modern neurorehabilitative treatment schemes. PMID:25624838

  1. JIGSAW PUZZLE IMPROVE FINE MOTOR ABILITIES OF UPPER EXTREMITIES IN POST-STROKE ISCHEMIC CLIENTS

    Directory of Open Access Journals (Sweden)

    Kusnanto Kusnanto

    2017-06-01

    Full Text Available Introduction: Ischemic stroke is a disease caused by focal cerebral ischemia, where is a decline in blood flow that needed for neuronal metabolism, leading to neurologic deficit include motor deficit such as fine motor skills impairment. Therapy of fine motor skills disorders is to improve motor function, prevent contractures and complications. These study aimed to identify the effect of playing Jigsaw Puzzle on muscle strength, extensive motion, and upper extremity fine motor skills in patients with ischemic stroke at Dr. Moewardi Hospital, Surakarta. Methods: Experimental Quasi pre-posttest one group control. The number of samples were 34 respondents selected using purposive sampling technique. The samples were divided into intervention and control groups. The intervention group was 17 respondents who were given standard treatment hospital and played Jigsaw Puzzle 2 times a day for six days. Control group is one respondent given by hospital standard therapy without given additional Jigsaw Puzzle game. Evaluation of these research is done on the first and seventh day for those groups. Result: The results showed that muscle strength, the range of joint motion and fine motor skills of upper extremities increased (p = 0.001 significantly after being given the Jigsaw Puzzle games. These means playing Jigsaw Puzzle increase muscle strength, the range of joint motion and upper extremity fine motor skill of ischemic stroke patients. Discussion and conclusion: Jigsaw puzzle game administration as additional rehabilitation therapy in upper extremity fine motor to minimize the occurrence of contractures and motor disorders in patients with ischemic stroke. Jigsaw puzzle game therapy capable of creating repetitive motion as a key of neurological rehabilitation in Ischemic Stroke. This study recommends using jigsaw puzzle game as one of intervention in the nursing care of Ischemic Stroke patients.

  2. The sensory side of post-stroke motor rehabilitation

    OpenAIRE

    Bolognini, Nadia; Russo, Cristina; Edwards, Dylan J.

    2016-01-01

    Contemporary strategies to promote motor recovery following stroke focus on repetitive voluntary movements. Although successful movement relies on efficient sensorimotor integration, functional outcomes often bias motor therapy toward motor-related impairments such as weakness, spasticity and synergies; sensory therapy and reintegration is implied, but seldom targeted. However, the planning and execution of voluntary movement requires that the brain extracts sensory information regarding body...

  3. associated neuron disease carCInoma Motor with

    African Journals Online (AJOL)

    1983-02-19

    Feb 19, 1983 ... re\\'ealed wasting of the temporalis muscle, upper motor neuron weakness of the ... left, there was bilateral wasting ofthe small muscles of the hands, .... disease with associated rectal adenocarcinoma and benign pros- tatic hypertrophy. Discussion. Motor neuron disease occurs in all parts of the world, with a.

  4. Synchronization of motor neurons during locomotion in the neonatal rat

    DEFF Research Database (Denmark)

    Tresch, Matthew C.; Kiehn, Ole

    2002-01-01

    We describe here the robust synchronization of motor neurons at a millisecond time scale during locomotor activity in the neonatal rat. Action potential activity of motor neuron pairs was recorded extracellularly using tetrodes during locomotor activity in the in vitro neonatal rat spinal cord. A...... synchronization described here might be involved in activity-dependent processes during development or in the coordination of individual motor neurons into a functional population underlying behavior.......We describe here the robust synchronization of motor neurons at a millisecond time scale during locomotor activity in the neonatal rat. Action potential activity of motor neuron pairs was recorded extracellularly using tetrodes during locomotor activity in the in vitro neonatal rat spinal cord....... Approximately 40% of motor neuron pairs recorded in the same spinal segment showed significant synchronization, with the duration of the central peak in cross-correlograms between motor neurons typically ranging between ∼ 30 and 100 msec. The percentage of synchronized motor neuron pairs was considerably higher...

  5. Motor neuron disease in blacks | Cosnett | South African Medical ...

    African Journals Online (AJOL)

    Motor neuron disease in blacks. JE Cosnett, PLA Bill, AI Bhigjee. Abstract. A series of 86 black, Indian and white patients with motor neuron disease were analysed retrospectively. Although the material does not allow statistically valid conclusions, there are sufficient cases among blacks to allow two prima facie observations ...

  6. Motor neuron disease associated with carcinoma | Gritzman | South ...

    African Journals Online (AJOL)

    Paraneoplastic complications are obscure and difficult to understand. The association of motor neuron disease and carcinoma may sometimes be more than coincidental, and 2 cases are described. One patient had motor neuron disease, limbic encephalitis (a recognized paraneoplastic disorder) and carcinoma of the ...

  7. Orofacial Apraxia in Motor Neuron Disease

    Science.gov (United States)

    Lobo, Patrícia Pita; Pinto, Susana; Rocha, Luz; Reimão, Sofia; de Carvalho, Mamede

    2013-01-01

    Introduction Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD). Results Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD. PMID:23569452

  8. Orofacial Apraxia in Motor Neuron Disease

    Directory of Open Access Journals (Sweden)

    Patrícia Pita Lobo

    2013-03-01

    Full Text Available Introduction: Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND. Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods: We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD. Results: Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD.

  9. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

    Science.gov (United States)

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-09-22

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: A clinical and brain imaging review

    NARCIS (Netherlands)

    van der Graaff, M. M.; de Jong, J. M. B. V.; Baas, F.; de Visser, M.

    2009-01-01

    There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary

  11. Spatial cognitive rehabilitation and motor recovery after stroke

    Science.gov (United States)

    Barrett, A.M.; Muzaffar, Tufail

    2014-01-01

    Purpose of review Stroke rehabilitation needs to take major steps forward to reduce functional disability for survivors. In this article, we suggest that spatial retraining might greatly increase the efficiency and efficacy of motor rehabilitation, directly addressing the burden and cost of paralysis after stroke. Recent findings Combining motor and cognitive treatment may be practical, as well as addressing needs after moderate–to-severe stroke. Spatial neglect could suppress motor recovery and reduce motor learning, even when patients receive appropriate rehabilitation to build strength, dexterity, and endurance. Spatial neglect rehabilitation acts to promote motor as well as visual-perceptual recovery. These findings, and previous underemphasized studies, make a strong case for combining spatial neglect treatment with traditional exercise training. Spatial neglect therapies might also help people who cannot participate in intensive movement therapies because of limited strength and endurance after stroke. Summary Spatial retraining, currently used selectively after right brain stroke, may be broadly useful after stroke to promote rapid motor recovery. PMID:25364954

  12. Contralesional Cortical Structural Reorganization Contributes to Motor Recovery after Sub-Cortical Stroke: A Longitudinal Voxel-Based Morphometry Study.

    Science.gov (United States)

    Cai, Jianxin; Ji, Qiling; Xin, Ruiqiang; Zhang, Dianping; Na, Xu; Peng, Ruchen; Li, Kuncheng

    2016-01-01

    Although changes in brain gray matter after stroke have been identified in some neuroimaging studies, lesion heterogeneity and individual variability make the detection of potential neuronal reorganization difficult. This study attempted to investigate the potential structural cortical reorganization after sub-cortical stroke using a longitudinal voxel-based gray matter volume (GMV) analysis. Eleven right-handed patients with first-onset, subcortical, ischemic infarctions involving the basal ganglia regions underwent structural magnetic resonance imaging in addition to National Institutes of Health Stroke Scale (NIHSS) and Motricity Index (MI) assessments in the acute (reorganization of the CL "cognitive" cortices might contribute to motor recovery after sub-cortical stroke.

  13. Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

    Science.gov (United States)

    Delva, Aline; Thakore, Nimish; Pioro, Erik P; Poesen, Koen; Saunders-Pullman, Rachel; Meijer, Inge A; Rucker, Janet C; Kissel, John T; Van Damme, Philip

    2017-12-01

    Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017. © 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

  14. Potential predictors of lower extremity impairments in motor coordination of stroke survivors.

    Science.gov (United States)

    Menezes, Kenia K; Scianni, Aline A; Faria-Fortini, Iza; Avelino, Patrick R; Carvalho, Augusto C; Faria, Christina D; Teixeira-Salmela, Luci F

    2016-06-01

    It is well recognized that the negative motor impairments following upper motor neuron damage, e.g., loss of strength and dexterity (motor coordination), mostly contribute to disability. Many factors may predict impairments in motor coordination (MC) and the identifications of these factors could help rehabilitation professionals to select variables to be considered in the evaluation and interventions aimed at improving MC of the lower limbs after stroke. To investigate the potential predictors of motor coordination (MC) of the paretic lower limb with stroke subjects, as assessed by the Lower Limb Motor Coordination Test (LEMOCOT). Cross-sectional, observational study. University laboratory. One hundred and six stroke subjects. The selected potential predictors of the LEMOCOT scores were age, gender, motor recovery and sensation of the lower limb, tonus of the knee extensor and plantar flexor muscles, and strength of the hip flexor and knee flexor/extensor muscles. Step-wise multiple regression was employed for analysis. Only motor recovery, tonus of the plantar flexor muscles, and age reached significance (PMotor recovery alone was able to explain 46% (F=89.0, Pmotor recovery was positively associated with the LEMOCOT scores, whereas the tonus of the plantar flexor muscles and age were negatively correlated. Motor recovery of the lower limb, tonus of the plantar flexor muscles, and age were significant predictors of MC of the paretic lower limb. These findings could help rehabilitation professionals to evaluate MC deficits and plan interventions aimed at improving MC of the lower limbs for stroke subjects, based upon the knowledge of the possible factors that could contribute to MC impairments.

  15. Neuronal mechanisms of motor learning and motor memory consolidation in healthy old adults

    NARCIS (Netherlands)

    Berghuis, K. M. M.; Veldman, M. P.; Solnik, S.; Koch, G.; Zijdewind, I.; Hortobagyi, T.

    It is controversial whether or not old adults are capable of learning new motor skills and consolidate the performance gains into motor memory in the offline period. The underlying neuronal mechanisms are equally unclear. We determined the magnitude of motor learning and motor memory consolidation

  16. Motor imagery and stroke rehabilitation : A critical discussion

    NARCIS (Netherlands)

    de Vries, Sjoerd; Mulder, Theo

    Motor disorders are a frequent consequence of stroke and much effort is invested in the re-acquisition of motor control. Although patients often regain some of their lost function after therapy, most remain chronically disabled. Functional recovery is achieved largely through reorganization

  17. Virtual reality applications for motor rehabilitation after stroke.

    Science.gov (United States)

    Sisto, Sue Ann; Forrest, Gail F; Glendinning, Diana

    2002-01-01

    Hemiparesis is the primary physical impairment underlying functional disability after stroke. A goal of rehabilitation is to enhance motor skill acquisition, which is a direct result of practice. However, frequency and duration of practice are limited in rehabilitation. Virtual reality (VR) is a computer technology that simulates real-life learning while providing augmented feedback and increased frequency, duration, and intensity of practiced tasks. The rate and extent of relearning of motor tasks could affect the duration, effectiveness, and cost of patient care. The purpose of this article is to review the use of VR training for motor rehabilitation after stroke.

  18. [The mirror neuron system in motor and sensory rehabilitation].

    Science.gov (United States)

    Oouchida, Yutaka; Izumi, Shinichi

    2014-06-01

    The discovery of the mirror neuron system has dramatically changed the study of motor control in neuroscience. The mirror neuron system provides a conceptual framework covering the aspects of motor as well as sensory functions in motor control. Previous studies of motor control can be classified as studies of motor or sensory functions, and these two classes of studies appear to have advanced independently. In rehabilitation requiring motor learning, such as relearning movement after limb paresis, however, sensory information of feedback for motor output as well as motor command are essential. During rehabilitation from chronic pain, motor exercise is one of the most effective treatments for pain caused by dysfunction in the sensory system. In rehabilitation where total intervention unifying the motor and sensory aspects of motor control is important, learning through imitation, which is associated with the mirror neuron system can be effective and suitable. In this paper, we introduce the clinical applications of imitated movement in rehabilitation from motor impairment after brain damage and phantom limb pain after limb amputation.

  19. Insm1a Regulates Motor Neuron Development in Zebrafish

    Directory of Open Access Journals (Sweden)

    Jie Gong

    2017-08-01

    Full Text Available Insulinoma-associated1a (insm1a is a zinc-finger transcription factor playing a series of functions in cell formation and differentiation of vertebrate central and peripheral nervous systems and neuroendocrine system. However, its roles on the development of motor neuron have still remained uncovered. Here, we provided evidences that insm1a was a vital regulator of motor neuron development, and provided a mechanistic understanding of how it contributes to this process. Firstly, we showed the localization of insm1a in spinal cord, and primary motor neurons (PMNs of zebrafish embryos by in situ hybridization, and imaging analysis of transgenic reporter line Tg(insm1a: mCherryntu805. Then we demonstrated that the deficiency of insm1a in zebrafish larvae lead to the defects of PMNs development, including the reduction of caudal primary motor neurons (CaP, and middle primary motor neurons (MiP, the excessive branching of motor axons, and the disorganized distance between adjacent CaPs. Additionally, knockout of insm1 impaired motor neuron differentiation in the spinal cord. Locomotion analysis showed that swimming activity was significantly reduced in the insm1a-null zebrafish. Furthermore, we showed that the insm1a loss of function significantly decreased the transcript levels of both olig2 and nkx6.1. Microinjection of olig2 and nkx6.1 mRNA rescued the motor neuron defects in insm1a deficient embryos. Taken together, these data indicated that insm1a regulated the motor neuron development, at least in part, through modulation of the expressions of olig2 and nkx6.1.

  20. Motor neuron degeneration correlates with respiratory dysfunction in SCA1.

    Science.gov (United States)

    Orengo, James P; van der Heijden, Meike E; Hao, Shuang; Tang, Jianrong; Orr, Harry T; Zoghbi, Huda Y

    2018-01-29

    Spinocerebellar ataxia type 1 (SCA1) is characterized by adult-onset cerebellar degeneration with attendant loss of motor coordination. Bulbar function is eventually impaired, and patients tend to die from inability to clear the airway. We asked whether motor neuron degeneration is at the root of bulbar dysfunction by studying SCA1 knock-in mice. We analyzed spinal cord and brainstem motor neurons in SCA1 knock-in (Atxn1 154Q ) mice at 1, 3, and 6 months of age. Specifically, we assessed breathing physiology, diaphragm histology and electromyography, and motor neuron histology and immunohistochemistry. Atxn1 154Q mice show progressive neuromuscular respiratory abnormalities, neurogenic changes in diaphragm, and motor neuron degeneration in the spinal cord and brainstem. The latter is accompanied by reactive astrocytosis and accumulation of Atxn1 aggregates in the motor neuron nuclei. This dovetails with previous observations in SCA1 patient tissue. Atxn1 154Q mice develop bulbar dysfunction because of motor neuron degeneration. These findings confirm the Atxn1 154Q line as a SCA1 model with face and construct validity for this understudied disease feature. Furthermore, this model is suitable to study the pathogenic mechanism driving motor neuron degeneration in SCA1 and perhaps other degenerative motor neuron diseases. From a clinical standpoint, the data indicate that pulmonary function testing and employment of non-invasive ventilator support could be beneficial in SCA1 patients. The physiological tests used in this study may serve as valuable biomarkers for future therapeutic interventions and clinical trials. © 2018. Published by The Company of Biologists Ltd.

  1. Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease.

    Science.gov (United States)

    Fisher, Karen M; Zaaimi, Boubker; Williams, Timothy L; Baker, Stuart N; Baker, Mark R

    2012-09-01

    In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15-30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15-30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control

  2. The sensory side of post-stroke motor rehabilitation.

    Science.gov (United States)

    Bolognini, Nadia; Russo, Cristina; Edwards, Dylan J

    2016-04-11

    Contemporary strategies to promote motor recovery following stroke focus on repetitive voluntary movements. Although successful movement relies on efficient sensorimotor integration, functional outcomes often bias motor therapy toward motor-related impairments such as weakness, spasticity and synergies; sensory therapy and reintegration is implied, but seldom targeted. However, the planning and execution of voluntary movement requires that the brain extracts sensory information regarding body position and predicts future positions, by integrating a variety of sensory inputs with ongoing and planned motor activity. Neurological patients who have lost one or more of their senses may show profoundly affected motor functions, even if muscle strength remains unaffected. Following stroke, motor recovery can be dictated by the degree of sensory disruption. Consequently, a thorough account of sensory function might be both prognostic and prescriptive in neurorehabilitation. This review outlines the key sensory components of human voluntary movement, describes how sensory disruption can influence prognosis and expected outcomes in stroke patients, reports on current sensory-based approaches in post-stroke motor rehabilitation, and makes recommendations for optimizing rehabilitation programs based on sensory stimulation.

  3. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    Science.gov (United States)

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  4. Neuroplasticity in the context of motor rehabilitation after stroke

    Science.gov (United States)

    Dimyan, Michael A.; Cohen, Leonardo G.

    2016-01-01

    Approximately one-third of patients with stroke exhibit persistent disability after the initial cerebrovascular episode, with motor impairments accounting for most poststroke disability. Exercise and training have long been used to restore motor function after stroke. Better training strategies and therapies to enhance the effects of these rehabilitative protocols are currently being developed for poststroke disability. The advancement of our understanding of the neuroplastic changes associated with poststroke motor impairment and the innate mechanisms of repair is crucial to this endeavor. Pharmaceutical, biological and electrophysiological treatments that augment neuroplasticity are being explored to further extend the boundaries of poststroke rehabilitation. Potential motor rehabilitation therapies, such as stem cell therapy, exogenous tissue engineering and brain–computer interface technologies, could be integral in helping patients with stroke regain motor control. As the methods for providing motor rehabilitation change, the primary goals of poststroke rehabilitation will be driven by the activity and quality of life needs of individual patients. This Review aims to provide a focused overview of neuroplasticity associated with poststroke motor impairment, and the latest experimental interventions being developed to manipulate neuroplasticity to enhance motor rehabilitation. PMID:21243015

  5. Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.

    Science.gov (United States)

    Lecomte, Marie-José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne-Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre-François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie

    2014-05-01

    Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. The in vivo contribution of motor neuron TrkB receptors to mutant SOD1 motor neuron disease.

    Science.gov (United States)

    Zhai, Jinbin; Zhou, Weiguo; Li, Jian; Hayworth, Christopher R; Zhang, Lei; Misawa, Hidemi; Klein, Rudiger; Scherer, Steven S; Balice-Gordon, Rita J; Kalb, Robert Gordon

    2011-11-01

    Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are widely expressed in the vertebrate nervous system and play a central role in mature neuronal function. In vitro BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults. Paradoxically, BDNF/TrkB signaling has also been shown, under certain in vitro circumstances, to render neurons vulnerable to insults. We show here that in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity. Mutant SOD1 mice lacking motor neuron TrkB live a month longer than controls and retain motor function for a longer period, particularly in the early phase of the disease. These effects are subserved by slowed motor neuron loss, persistence of neuromuscular junction integrity and reduced astrocytic and microglial reactivity within the spinal cord. These results suggest that manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases.

  7. Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons.

    Science.gov (United States)

    Machado, Carolina Barcellos; Kanning, Kevin C; Kreis, Patricia; Stevenson, Danielle; Crossley, Martin; Nowak, Magdalena; Iacovino, Michelina; Kyba, Michael; Chambers, David; Blanc, Eric; Lieberam, Ivo

    2014-02-01

    Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations.

  8. Diagnosis and management of motor neurone disease.

    Science.gov (United States)

    Orrell, Richard W

    2016-09-01

    Motor neurone disease is a rapidly progressive and fatal neurodegenerative condition which causes progressive weakness, with normal sensation. It can occur at any age but is more frequent with increasing age. Key clinical presentations include bulbar (slurred or difficult speech, problems swallowing, tongue fasciculation), limb (typically in one limb with weakness and muscle wasting), respiratory (breathlessness, chest muscle fasciculation) and cognitive features (behavioural change, emotional lability, features of frontotemporal dementia). Although survival is typically three to five years from symptom onset, there is significant individual variation. Rarely, survival may be 20 years or longer. Favourable features include a limb rather than a bulbar presentation, preserved weight and respiratory function, younger age of onset and longer time from fist symptom to diagnosis. The patient should be linked to a multidisciplinary team able to provide support from the start with a designated individual as the point of contact, with regular, coordinated assessments, as the patient's needs change and their condition progresses. Gastrostomy is an important supportive intervention which maximizes nutrition, and minimizes aspiration and chest infection. Adequate nutrition and hydration is key to maximizing health and survival. It is possible for a patient to control a computer and speech by eye. movement alone. An important consideration is voice banking where the patient may store their voice before there is difficulty with speech so that it can be used at a later stage if they need a communication aid. Impaired cough and retention of respiratory secretions is frequent in the later stages, and may be managed with physiotherapy. The patient should be referred for expert respiratory assessment if needed.

  9. Mammalian motor neurons corelease glutamate and acetylcholine at central synapses

    DEFF Research Database (Denmark)

    Nishimaru, Hiroshi; Restrepo, Carlos Ernesto; Ryge, Jesper

    2005-01-01

    Motor neurons (MNs) are the principal neurons in the mammalian spinal cord whose activities cause muscles to contract. In addition to their peripheral axons, MNs have central collaterals that contact inhibitory Renshaw cells and other MNs. Since its original discovery > 60 years ago, it has been...

  10. Axonal regeneration and neuronal function are preserved in motor neurons lacking ß-actin in vivo.

    Directory of Open Access Journals (Sweden)

    Thomas R Cheever

    2011-03-01

    Full Text Available The proper localization of ß-actin mRNA and protein is essential for growth cone guidance and axon elongation in cultured neurons. In addition, decreased levels of ß-actin mRNA and protein have been identified in the growth cones of motor neurons cultured from a mouse model of Spinal Muscular Atrophy (SMA, suggesting that ß-actin loss-of-function at growth cones or pre-synaptic nerve terminals could contribute to the pathogenesis of this disease. However, the role of ß-actin in motor neurons in vivo and its potential relevance to disease has yet to be examined. We therefore generated motor neuron specific ß-actin knock-out mice (Actb-MNsKO to investigate the function of ß-actin in motor neurons in vivo. Surprisingly, ß-actin was not required for motor neuron viability or neuromuscular junction maintenance. Skeletal muscle from Actb-MNsKO mice showed no histological indication of denervation and did not significantly differ from controls in several measurements of physiologic function. Finally, motor axon regeneration was unimpaired in Actb-MNsKO mice, suggesting that ß-actin is not required for motor neuron function or regeneration in vivo.

  11. Functional significance of ipsilesional motor deficits after unilateral stroke.

    Science.gov (United States)

    Chestnut, Caitilin; Haaland, Kathleen Y

    2008-01-01

    To determine whether ipsilesional motor skills, which have been related to independent functioning, are present chronically after unilateral stroke and are more common in people with apraxia than in those without apraxia. Observational cohort comparing the performance of an able-bodied control group, stroke patients with left- or right-hemisphere damage matched for lesion volume, and left-hemisphere stroke patients with and without ideomotor limb apraxia. Primary care Veterans Affairs and private medical center. Volunteer right-handed sample; stroke patients with left- or right-hemisphere damage about 4 years poststroke; a control group of demographically matched, able-bodied adults. Not applicable. Total time to perform the (1) Williams doors test and the (2) timed manual performance test (TMPT), which includes parts of the Jebsen-Taylor Hand Function Test. Ipsilesional motor deficits were present after left- or right-hemisphere stroke when using both measures, but deficits were consistently more common in patients with limb apraxia only for the TMPT. These findings add to a growing literature that suggests that ipsilesional motor deficits may have a functional impact in unilateral stroke patients, especially in patients with ideomotor limb apraxia.

  12. Motor cortex stimulation therapy for post-stroke weakness

    International Nuclear Information System (INIS)

    Ogura, Koichiro; Aoshima, Chihiro; Yamanouchi, Takashi; Tachibana, Eiji

    2009-01-01

    Motor cortex stimulation (MCS) delivered concurrently with rehabilitation therapy may enhance motor recovery following stroke. We investigated the effects of MCS on the recovery from upper extremity paresis in patients with chronic stroke. In 12 patients who had moderate arm and finger paresis at more than 4 months after stroke, an electrode was placed through a small craniotomy on the epidural space of the motor cortex that was identified using functional MRI. MCS during occupational therapy for one hour was performed 3 times a day for at least 4 weeks. The mean scores for Fugl-Meyer assessments of the arm improved, from 37 preoperatively to 46 postoperatively. The mean grip strength improved from 3.25 to 9.0 kg. All patients appeared satisfactory in their results because they recognized an improvement of arm function. Although the mechanism of the beneficial effects of MCS on recovery after stroke has not been well known, the neuroplasticity might play a important role. In a few cases of the present series, it was observed that the hand motor cortex area detected on functional MRI had been enlarged after MCS therapy. MCS could become a novel neurosurgical treatment modality for the chronic post-stroke weakness. (author)

  13. Changes of motor recovery in chronic stroke patients

    Directory of Open Access Journals (Sweden)

    Rodríguez-Lázaro, Álvaro Enrique

    2016-04-01

    Full Text Available Introduction: Few studies have evaluated changes in motor recovery during the chronic phase of stroke. Objective: To determine changes in motor function in chronic stroke survivors. Materials and methods: A retrospective-descriptive analysis was done of the records of 47 patients with motor sequelae of stroke with clinical evolution longer than 6 months (average: 8 months. Functional changes obtained between two consecutive records (average time between assessments: 6 months in scores of Fugl-Meyer Motor Scale (FM, Box and Block Test, PASS, Modified Rankin Scale (MRS, Barthel Index, Composite Functional Index, Modified Ashworth Scale were analyzed. Results: The whole group had significant changes toward functional motor recovery in all scales (p < 0.01, except for the FM in the lower limb. However, the sizes of the effect were small. In patients with evolution longer than 12 months, both the size of effects and statistical significance diminished. Conclusion: After six months of evolution, patients with motor sequelae of CVA show small changes toward functional motor recovery, which are statistically significant until twelve months.

  14. Reward and punishment enhance motor adaptation in stroke.

    Science.gov (United States)

    Quattrocchi, Graziella; Greenwood, Richard; Rothwell, John C; Galea, Joseph M; Bestmann, Sven

    2017-09-01

    The effects of motor learning, such as motor adaptation, in stroke rehabilitation are often transient, thus mandating approaches that enhance the amount of learning and retention. Previously, we showed in young individuals that reward and punishment feedback have dissociable effects on motor adaptation, with punishment improving adaptation and reward enhancing retention. If these findings were able to generalise to patients with stroke, they would provide a way to optimise motor learning in these patients. Therefore, we tested this in 45 patients with chronic stroke allocated in three groups. Patients performed reaching movements with their paretic arm with a robotic manipulandum. After training (day 1), day 2 involved adaptation to a novel force field. During the adaptation phase, patients received performance-based feedback according to the group they were allocated: reward, punishment or no feedback (neutral). On day 3, patients readapted to the force field but all groups now received neutral feedback. All patients adapted, with reward and punishment groups displaying greater adaptation and readaptation than the neutral group, irrespective of demographic, cognitive or functional differences. Remarkably, the reward and punishment groups adapted to similar degree as healthy controls. Finally, the reward group showed greater retention. This study provides, for the first time, evidence that reward and punishment can enhance motor adaptation in patients with stroke. Further research on reinforcement-based motor learning regimes is warranted to translate these promising results into clinical practice and improve motor rehabilitation outcomes in patients with stroke. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared. © 2015 Anatomical Society.

  16. A Schwann cell mitogen accompanying regeneration of motor neurons.

    Science.gov (United States)

    Livesey, F J; O'Brien, J A; Li, M; Smith, A G; Murphy, L J; Hunt, S P

    1997-12-11

    Motor neurons are the only adult mammalian neurons of the central nervous system to regenerate following injury. This ability is dependent on the environment of the peripheral nerve and an intrinsic capacity of motor neurons for regrowth. We report here the identification, using a technique known as messenger RNA differential display, of an extracellular signalling molecule, previously described as the pancreatic secreted protein Reg-2, that is expressed solely in regenerating and developing rat motor and sensory neurons. Axon-stimulated Schwann cell proliferation is necessary for successful regeneration, and we show that Reg-2 is a potent Schwann cell mitogen in vitro. In vivo, Reg-2 protein is transported along regrowing axons and inhibition of Reg-2 signalling significantly retards the regeneration of Reg-2-containing axons. During development, Reg-2 production by motor and sensory neurons is regulated by contact with peripheral targets. Strong candidates for peripheral factors regulating Reg-2 production are cytokines of the LIF/CNTF family, because Reg-2 is not expressed in developing motor or sensory neurons of mice carrying a targeted disruption of the LIF receptor gene, a common component of the receptor complexes for all of the LIF/CNTF family.

  17. Recovery of Motor Imagery Ability in Stroke Patients

    Directory of Open Access Journals (Sweden)

    Sjoerd de Vries

    2011-01-01

    Full Text Available Objective. To investigate whether motor imagery ability recovers in stroke patients and to see what the relationship is between different types of imagery and motor functioning after stroke. Methods. 12 unilateral stroke patients were measured at 3 and 6 weeks poststroke on 3 mental imagery tasks. Arm-hand function was evaluated using the Utrecht Arm-Hand task and the Brunnström Fugl-Meyer Scale. Age-matched healthy individuals (N=10 were included as controls. Results. Implicit motor imagery ability and visual motor imagery ability improved significantly at 6 weeks compared to 3 weeks poststroke. Conclusion. Our study shows that motor imagery can recover in the first weeks after stroke. This indicates that a group of patients who might not be initially selected for mental practice can, still later in the rehabilitation process, participate in mental practice programs. Moreover, our study shows that mental imagery modalities can be differently affected in individual patients and over time.

  18. Motor imagery ability in stroke patients : the relationship between implicit and explicit motor imagery measures

    NARCIS (Netherlands)

    de Vries, Sjoerd; Tepper, Marga; Feenstra, Wya; Oosterveld, Hanneke; Boonstra, Anne M.; Otten, Bert

    2013-01-01

    There is little consensus on how motor imagery ability should be measured in stroke patients. In particular it is unclear how two methods tapping different aspects of the motor imagery process relate to each other. The aim of this study was to investigate the relationship between implicit and

  19. Proportional Motor Recovery After Stroke: Implications for Trial Design.

    Science.gov (United States)

    Stinear, Cathy M; Byblow, Winston D; Ackerley, Suzanne J; Smith, Marie-Claire; Borges, Victor M; Barber, P Alan

    2017-03-01

    Recovery of upper-limb motor impairment after first-ever ischemic stroke is proportional to the degree of initial impairment in patients with a functional corticospinal tract (CST). This study aimed to investigate whether proportional recovery occurs in a more clinically relevant sample including patients with intracerebral hemorrhage and previous stroke. Patients with upper-limb weakness were assessed 3 days and 3 months poststroke with the Fugl-Meyer scale. Transcranial magnetic stimulation was used to test CST function, and patients were dichotomized according to the presence of motor evoked potentials in the paretic wrist extensors. Linear regression modeling of Δ Fugl-Meyer score between 3 days and 3 months was performed, with predictors including initial impairment (66 - baseline Fugl-Meyer score), age, sex, stroke type, previous stroke, comorbidities, and upper-limb therapy dose. One hundred ninety-two patients were recruited, and 157 completed 3-month follow-up. Patients with a functional CST made a proportional recovery of 63% (95% confidence interval, 55%-70%) of initial motor impairment. The recovery of patients without a functional CST was not proportional to initial impairment and was reduced by greater CST damage. Recovery of motor impairment in patients with intact CST is proportional to initial impairment and unaffected by previous stroke, type of stroke, or upper-limb therapy dose. Novel interventions that interact with the neurobiological mechanisms of recovery are needed. The generalizability of proportional recovery is such that patients with intracerebral hemorrhage and previous stroke may usefully be included in interventional rehabilitation trials. URL: http://www.anzctr.org.au. Unique identifier: ANZCTR12611000755932. © 2017 American Heart Association, Inc.

  20. Spasticity, Motor Recovery, and Neural Plasticity after Stroke.

    Science.gov (United States)

    Li, Sheng

    2017-01-01

    Spasticity and weakness (spastic paresis) are the primary motor impairments after stroke and impose significant challenges for treatment and patient care. Spasticity emerges and disappears in the course of complete motor recovery. Spasticity and motor recovery are both related to neural plasticity after stroke. However, the relation between the two remains poorly understood among clinicians and researchers. Recovery of strength and motor function is mainly attributed to cortical plastic reorganization in the early recovery phase, while reticulospinal (RS) hyperexcitability as a result of maladaptive plasticity, is the most plausible mechanism for poststroke spasticity. It is important to differentiate and understand that motor recovery and spasticity have different underlying mechanisms. Facilitation and modulation of neural plasticity through rehabilitative strategies, such as early interventions with repetitive goal-oriented intensive therapy, appropriate non-invasive brain stimulation, and pharmacological agents, are the keys to promote motor recovery. Individualized rehabilitation protocols could be developed to utilize or avoid the maladaptive plasticity, such as RS hyperexcitability, in the course of motor recovery. Aggressive and appropriate spasticity management with botulinum toxin therapy is an example of how to create a transient plastic state of the neuromotor system that allows motor re-learning and recovery in chronic stages.

  1. A review: Motor rehabilitation after stroke with control based on human intent.

    Science.gov (United States)

    Li, Min; Xu, Guanghua; Xie, Jun; Chen, Chaoyang

    2018-02-01

    Strokes are a leading cause of acquired disability worldwide, and there is a significant need for novel interventions and further research to facilitate functional motor recovery in stroke patients. This article reviews motor rehabilitation methods for stroke survivors with a focus on rehabilitation controlled by human motor intent. The review begins with the neurodevelopmental principles of motor rehabilitation that provide the neuroscientific basis for intuitively controlled rehabilitation, followed by a review of methods allowing human motor intent detection, biofeedback approaches, and quantitative motor rehabilitation assessment. Challenges for future advances in motor rehabilitation after stroke using intuitively controlled approaches are addressed.

  2. Robot-based hand motor therapy after stroke.

    Science.gov (United States)

    Takahashi, Craig D; Der-Yeghiaian, Lucy; Le, Vu; Motiwala, Rehan R; Cramer, Steven C

    2008-02-01

    Robots can improve motor status after stroke with certain advantages, but there has been less emphasis to date on robotic developments for the hand. The goal of this study was to determine whether a hand-wrist robot would improve motor function, and to evaluate the specificity of therapy effects on brain reorganization. Subjects with chronic stroke producing moderate right arm/hand weakness received 3 weeks therapy that emphasized intense active movement repetition as well as attention, speed, force, precision and timing, and included virtual reality games. Subjects initiated hand movements. If necessary, the robot completed movements, a feature available at all visits for seven of the subjects and at the latter half of visits for six of the subjects. Significant behavioural gains were found at end of treatment, for example, in Action Research Arm Test (34 +/- 20 to 38 +/- 19, Parm motor Fugl-Meyer score (45 +/- 10 to 52 +/- 10, P robotic assistance in all sessions as compared to those receiving robotic assistance in half of sessions. The grasp task practiced during robotic therapy, when performed during functional MRI, showed increased sensorimotor cortex activation across the period of therapy, while a non-practiced task, supination/pronation, did not. A robot-based therapy showed improvements in hand motor function after chronic stroke. Reorganization of motor maps during the current therapy was task-specific, a finding useful when considering generalization of rehabilitation therapy.

  3. The spectrum of lower motor neuron syndromes : classification, natural course and treatment

    NARCIS (Netherlands)

    Berg-Vos, R.M. van den

    2002-01-01

    This thesis focusses on patients with lower motor neuron syndromes. This relatively rare group of syndromes is clinically not well described and the pathogenesis is largely unknown. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) or motor

  4. Neural network remodeling underlying motor map reorganization induced by rehabilitative training after ischemic stroke.

    Science.gov (United States)

    Okabe, Naohiko; Shiromoto, Takashi; Himi, Naoyuki; Lu, Feng; Maruyama-Nakamura, Emi; Narita, Kazuhiko; Iwachidou, Nobuhisa; Yagita, Yoshiki; Miyamoto, Osamu

    2016-12-17

    Motor map reorganization is believed to be one mechanism underlying rehabilitation-induced functional recovery. Although the ipsilesional secondary motor area has been known to reorganize motor maps and contribute to rehabilitation-induced functional recovery, it is unknown how the secondary motor area is reorganized by rehabilitative training. In the present study, using skilled forelimb reaching tasks, we investigated neural network remodeling in the rat rostral forelimb area (RFA) of the secondary motor area during 4weeks of rehabilitative training. Following photothrombotic stroke in the caudal forelimb area (CFA), rehabilitative training led to task-specific recovery and motor map reorganization in the RFA. A second injury to the RFA resulted in reappearance of motor deficits. Further, when both the CFA and RFA were destroyed simultaneously, rehabilitative training no longer improved task-specific recovery. In neural tracer studies, although rehabilitative training did not alter neural projection to the RFA from other brain areas, rehabilitative training increased neural projection from the RFA to the lower spinal cord, which innervates the muscles in the forelimb. Double retrograde tracer studies revealed that rehabilitative training increased the neurons projecting from the RFA to both the upper cervical cord, which innervates the muscles in the neck, trunk, and part of the proximal forelimb, and the lower cervical cord. These results suggest that neurons projecting to the upper cervical cord provide new connections to the denervated forelimb area of the spinal cord, and these new connections may contribute to rehabilitation-induced task-specific recovery and motor map reorganization in the secondary motor area. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Maturation of Spinal Motor Neurons Derived from Human Embryonic Stem Cells

    Science.gov (United States)

    Takazawa, Tomonori; Croft, Gist F.; Amoroso, Mackenzie W.; Studer, Lorenz; Wichterle, Hynek; MacDermott, Amy B.

    2012-01-01

    Our understanding of motor neuron biology in humans is derived mainly from investigation of human postmortem tissue and more indirectly from live animal models such as rodents. Thus generation of motor neurons from human embryonic stem cells and human induced pluripotent stem cells is an important new approach to model motor neuron function. To be useful models of human motor neuron function, cells generated in vitro should develop mature properties that are the hallmarks of motor neurons in vivo such as elaborated neuronal processes and mature electrophysiological characteristics. Here we have investigated changes in morphological and electrophysiological properties associated with maturation of neurons differentiated from human embryonic stem cells expressing GFP driven by a motor neuron specific reporter (Hb9::GFP) in culture. We observed maturation in cellular morphology seen as more complex neurite outgrowth and increased soma area over time. Electrophysiological changes included decreasing input resistance and increasing action potential firing frequency over 13 days in vitro. Furthermore, these human embryonic stem cell derived motor neurons acquired two physiological characteristics that are thought to underpin motor neuron integrated function in motor circuits; spike frequency adaptation and rebound action potential firing. These findings show that human embryonic stem cell derived motor neurons develop functional characteristics typical of spinal motor neurons in vivo and suggest that they are a relevant and useful platform for studying motor neuron development and function and for modeling motor neuron diseases. PMID:22802953

  6. Diffusional Kurtosis Imaging and Motor Outcome in Acute Ischemic Stroke.

    Science.gov (United States)

    Spampinato, M V; Chan, C; Jensen, J H; Helpern, J A; Bonilha, L; Kautz, S A; Nietert, P J; Feng, W

    2017-07-01

    Motor impairment is the most common deficit after stroke. Our aim was to evaluate whether diffusional kurtosis imaging can detect corticospinal tract microstructural changes in the acute phase for patients with first-ever ischemic stroke and motor impairment and to assess the correlations between diffusional kurtosis imaging-derived diffusion metrics for the corticospinal tract and motor impairment 3 months poststroke. We evaluated 17 patients with stroke who underwent brain MR imaging including diffusional kurtosis imaging within 4 days after the onset of symptoms. Neurologic evaluation included the Fugl-Meyer Upper Extremity Motor scale in the acute phase and 3 months poststroke. For the corticospinal tract in the lesioned and contralateral hemispheres, we estimated with diffusional kurtosis imaging both pure diffusion metrics, such as the mean diffusivity and mean kurtosis, and model-dependent quantities, such as the axonal water fraction. We evaluated the correlations between corticospinal tract diffusion metrics and the Fugl-Meyer Upper Extremity Motor scale at 3 months. Among all the diffusion metrics, the largest percentage signal changes of the lesioned hemisphere corticospinal tract were observed with axial kurtosis, with an average 12% increase compared with the contralateral corticospinal tract. The strongest associations between the 3-month Fugl-Meyer Upper Extremity Motor scale score and diffusion metrics were found for the lesioned/contralateral hemisphere corticospinal tract mean kurtosis (ρ = -0.85) and axial kurtosis (ρ = -0.78) ratios. This study was designed to be one of hypothesis generation. Diffusion metrics related to kurtosis were found to be more sensitive than conventional diffusivity metrics to early poststroke corticospinal tract microstructural changes and may have potential value in the prediction of motor impairment at 3 months. © 2017 by American Journal of Neuroradiology.

  7. Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease

    Science.gov (United States)

    2016-01-01

    Background People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. Objective This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. Methods An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free-text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. Results Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. Conclusions People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best

  8. Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease.

    Science.gov (United States)

    Mackenzie, Lynette; Bhuta, Prarthna; Rusten, Kim; Devine, Janet; Love, Anna; Waterson, Penny

    2016-01-25

    People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free-text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best communication technology options as early as possible

  9. Progranulin is expressed within motor neurons and promotes neuronal cell survival

    Directory of Open Access Journals (Sweden)

    Kay Denis G

    2009-10-01

    Full Text Available Abstract Background Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival. Results In situ hybridisation and immunohistochemical techniques revealed that the progranulin gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human progranulin gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months. This is mediated at least in part through

  10. Parietal operculum and motor cortex activities predict motor recovery in moderate to severe stroke

    Directory of Open Access Journals (Sweden)

    Firdaus Fabrice Hannanu

    2017-01-01

    In subacute stroke, fMRI brain activity related to passive movement measured in a sensorimotor network defined by activity during voluntary movement predicted motor recovery better than baseline motor-FMS alone. Furthermore, fMRI sensorimotor network activity measures considered alone allowed excellent clinical recovery prediction and may provide reliable biomarkers for assessing new therapies in clinical trial contexts. Our findings suggest that neural reorganization related to motor recovery from moderate to severe stroke results from balanced changes in ipsilesional MI (BA4a and a set of phylogenetically more archaic sensorimotor regions in the ventral sensorimotor trend, in which OP1 and OP4 processes may complement the ipsilesional dorsal motor cortex in achieving compensatory sensorimotor recovery.

  11. What is happening to motor neuron disease in Nigeria? | Imam ...

    African Journals Online (AJOL)

    Conclusions: The frequency of motor neuron disease appears to have declined considerably. While the onset remains in the younger age group, the male predominance has remarkably increased. The proportion of amyotrophic lateral sclerosis has increased from 80 to 100% of cases. Trauma, previously reported to be an ...

  12. Mirror neurons: reflecting on the motor cortex and spinal cord.

    Science.gov (United States)

    Schieber, Marc H

    2013-02-18

    Neurons in the monkey motor cortex that project to the spinal cord to control particular muscle contractions and movements have been found to discharge again while the monkey simply watches another primate make similar movements: monkey see; monkey not do. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Dysarthria of Motor Neuron Disease: Clinician Judgments of Severity.

    Science.gov (United States)

    Seikel, J. Anthony; And Others

    1990-01-01

    This study investigated the relationship between the temporal-acoustic parameters of the speech of 15 adults with motor neuron disease. Differences in predictions of the progression of the disease and clinician judgments of dysarthria severity were found to relate to the linguistic systems of both speaker and judge. (Author/JDD)

  14. Bilateral lower motor neuron facial nerve palsy due to HIV ...

    African Journals Online (AJOL)

    A 34-year-old-woman presented with acute onset of headache and bilateral facial nerve paralysis. On examination bilateral lower motor neuron 7th cranial nerve palsy in keeping with bilateral Bell's palsy was apparent. Investigations showed aseptic meningitis, with a low CD4 count of 352 cells/μl and an elevated viral load ...

  15. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    Science.gov (United States)

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  16. Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients.

    Science.gov (United States)

    Rastgoo, Maryam; Naghdi, Sofia; Nakhostin Ansari, Noureddin; Olyaei, Gholamreza; Jalaei, Shohreh; Forogh, Bijan; Najari, Hamidreza

    2016-09-01

    To investigate the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on lower extremity (LE) spasticity, motor function and motor neurone excitability in chronic stroke patients. This study was a randomised sham-controlled cross-over trial with 1-week follow-up. A total of 20 post-stroke patients were randomised to receive active (n = 10) or sham (n = 10) rTMS. Fourteen of them (7 in each group) crossed over to the sham or active rTMS after a washout period of 1 month. Interventions consist of five consecutive daily sessions of active or sham rTMS to the unaffected lower extremity motor area (1000 pulses; 1 Hz; 90% of the tibialis anterior motor threshold). Outcome measures were modified modified ashworth scale (MMAS), the H-reflex, lower extremity section of Fugl-Mayer assessment (LE-FMA) and timed UP and GO (TUG) test. All outcomes were measured at three levels in each intervention period: pre- and post-intervention and 1-week follow-up. Friedman's test revealed significant improvement in MMAS score only after active rTMS. This improvement lasted for one week after the active rTMS. Repeated measure analysis of variance (ANOVA) showed significant time*intervention interaction for LE-FMA. There are no differences between groups for the MMAS and LE-FMA. No significant change in Hmax/Mmax ratio and TUG test was noted. Low-frequency rTMS over the LE motor area can improve clinical measures of muscle spasticity and motor function. More studies are needed to clarify the changes underlying this improvement in spasticity. Implications for Rehabilitation Spasticity is a common disorder and one of the causes of long-term disability after stroke. Physical therapy modalities, oral medications, focal intervention and surgical procedures have been used for spasticity reduction. Beneficial effect of the repetitive transcranial magnetic stimulation (rTMS) for post-stroke upper extremity spasticity reduction and motor function improvement was

  17. Primary Motor Neuron Culture to Promote Cellular Viability and Myelination.

    Science.gov (United States)

    Suh, Jun-Kyo Francis; Hyung, Sujin

    2018-01-01

    A culture system that can recapitulate myelination in vitro will not only help us to better understand the mechanism of myelination and demyelination but also identify possible therapeutic interventions for treating demyelinating diseases. Here, we introduce a simple and reproducible myelination culture system using mouse motor neurons (MNs) and Schwann cells (SCs). Dissociated motor neurons are plated on a feeder layer of SCs, which interact with and wrap around the axons of MNs as they differentiate in culture. In our MN-SC co-culture system, MNs survive over 3 weeks and extend long axons. Both viability and axon growth of MNs in the co-culture are markedly enhanced as compared to those of MN monocultures. Co-labeling of myelin basic proteins and neuronal cell microtubules reveals that SCs form myelin sheaths by wrapping around the axons of MNs.

  18. Transcriptomics of aged Drosophila motor neurons reveals a matrix metalloproteinase that impairs motor function.

    Science.gov (United States)

    Azpurua, Jorge; Mahoney, Rebekah E; Eaton, Benjamin A

    2018-02-07

    The neuromuscular junction (NMJ) is responsible for transforming nervous system signals into motor behavior and locomotion. In the fruit fly Drosophila melanogaster, an age-dependent decline in motor function occurs, analogous to the decline experienced in mice, humans, and other mammals. The molecular and cellular underpinnings of this decline are still poorly understood. By specifically profiling the transcriptome of Drosophila motor neurons across age using custom microarrays, we found that the expression of the matrix metalloproteinase 1 (dMMP1) gene reproducibly increased in motor neurons in an age-dependent manner. Modulation of physiological aging also altered the rate of dMMP1 expression, validating dMMP1 expression as a bona fide aging biomarker for motor neurons. Temporally controlled overexpression of dMMP1 specifically in motor neurons was sufficient to induce deficits in climbing behavior and cause a decrease in neurotransmitter release at neuromuscular synapses. These deficits were reversible if the dMMP1 expression was shut off again immediately after the onset of motor dysfunction. Additionally, repression of dMMP1 enzymatic activity via overexpression of a tissue inhibitor of metalloproteinases delayed the onset of age-dependent motor dysfunction. MMPs are required for proper tissue architecture during development. Our results support the idea that matrix metalloproteinase 1 is acting as a downstream effector of antagonistic pleiotropy in motor neurons and is necessary for proper development, but deleterious when reactivated at an advanced age. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. Motor Recovery of the Affected Hand in Subacute Stroke Correlates with Changes of Contralesional Cortical Hand Motor Representation

    Directory of Open Access Journals (Sweden)

    Jitka Veldema

    2017-01-01

    Full Text Available Objective. To investigate the relationship between changes of cortical hand motor representation and motor recovery of the affected hand in subacute stroke. Methods. 17 patients with motor impairment of the affected hand were enrolled in an in-patient neurological rehabilitation program. Hand motor function tests (Wolf Motor Function Test, Action Research Arm Test and neurophysiological evaluations (resting motor threshold, motor evoked potentials, motor map area size, motor map area volume, and motor map area location were obtained from both hands and hemispheres at baseline and two, four, and six weeks of in-patient rehabilitation. Results. There was a wide spectrum of hand motor impairment at baseline and hand motor recovery over time. Hand motor function and recovery correlated significantly with (i reduction of cortical excitability, (ii reduction in size and volume of cortical hand motor representation, and (iii a medial and anterior shift of the center of gravity of cortical hand motor representation within the contralesional hemisphere. Conclusion. Recovery of motor function of the affected hand after stroke is accompanied by definite changes in excitability, size, volume, and location of hand motor representation over the contralesional primary motor cortex. These measures may serve as surrogate markers for the outcome of hand motor rehabilitation after stroke.

  20. A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations

    NARCIS (Netherlands)

    Beeldman, Emma; van der Kooi, Anneke J.; de Visser, Marianne; van Maarle, Merel C.; van Ruissen, Fred; Baas, Frank

    2015-01-01

    Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin

  1. Magnetic resonance imaging applied to motor neuron disease

    International Nuclear Information System (INIS)

    Markarian, Maria F.; Villarroal, Gonzalo M.; Giavitto, Enrique; Nagel, Jorge

    2005-01-01

    Objective: Differentiate Motor Neuron Disease by MRI. Material and Methods: 10 patients were studied, 7 patients had a diagnosis of definite ALS by the El Escorial criteria, 2 patients had lower motor neuron signs (LMN) and hyperreflexia and one patient had LMN signs without pain. MRI was performed: slices brain: Sagittal T1-weighted, sagittal and axial FSE T2, axial and coronal FLAIR, diffusion, singlevoxel spectroscopy in protuberances. Functional MRI with motor test; slices in cervical spine: Sagittal T1-weighted, sagittal and axial FSE T2, sagittal FSIR. Results: The 7 patients with definite ALS by El Escorial criteria and 2 patients with LMN signs and hyperreflexia: hyperintensity signal in FSE T2 and FLAIR extending from the motor cortex down to the corona radiate, posterior limb of internal capsules, cerebral peduncles and protuberance base; FSE T2: hypointensity sign in motor cortex; elevation in diffusivity and hyperintensity signal in ADC in posterior limb of internal capsule; reduction of NAA, high levels of Glutamine-Glutamate and of Colina. One of these 9 patients showed disc hernia in C4-5, and other patient in C3-C4, C4-C5 without cord lesion. The patient with LMN signs without pain showed normal brain and disc hernia C5-C6, hypertrophy yellow ligament, anterior-posterior diminution of medullar canal, hyperintensity signal in spine cord in the same level in sagittal FSIR. fMRI: increase signal in contralateral, ipsilateral motor area, and areas involved in initiation and planning movement. Conclusion: MRI allow differentiation between ALS and myelopathy cervical spondylitis and others motor neuron disease. (author) [es

  2. Mirror neurons: action observation treatment as a tool in stroke rehabilitation.

    Science.gov (United States)

    Franceschini, M; Agosti, M; Cantagallo, A; Sale, P; Mancuso, M; Buccino, G

    2010-12-01

    The observation of actions performed by others activate in an observer the same neural structures (including mirror neurons) as when he/she actually performs the same actions. The aim of the present study was to assess whether action observation treatment may improve upper limb motor impairment in chronic stroke patients. This was an observational study. Patients were recruited by three Italian Centres for Neurorehabilitation between 2006 and 2008. Twenty-eight chronic stroke patients with upper limb impairment have undergone for four weeks, five days a week, a rehabilitation treatment based on observation of video-clips presenting hand daily actions, followed by the imitation of those same actions with the affected limb. Functional evaluation by means of Modified Barthel Index (MBI), Frenchay Arm Test (FAT) and Fugl Meyer (FM) was carried out twice before treatment (BT1 and BT2), at an interval of 15 days, then after treatment (AT1) and finally at a two-month follow-up (AT2). Wilcoxon Signed Rank test was applied to test differences between scores obtained from functional scales before and after treatment (BT1 vs. BT2; BT2 vs. AT1; AT1 vs. AT2). In all scales, scores did not differ when comparing BT1 with BT2. Scores improved significantly in all scales at AT1 as compared to BT2 (MBI, P=0.026; FAT, P=0.005; FM, P=0.001). This improvement was still present at the two-month follow-up as testified by no score difference between AT1 and AT2. Action Observation Treatment may become a useful strategy in the rehabilitation of stroke patients. The present preliminary study suggests that stimulation of neural structures (including mirror neurons), activated when the patients actually perform the same actions as those observed could constitute a good alternative rehabilitative approach in chronic stroke patients.

  3. The Neuronal Network Orchestration behind Motor Behaviors

    DEFF Research Database (Denmark)

    Petersen, Peter Christian

    behaviors from a premotor network with recurrent connections, which is operating in the irregular regime. Our experimental findings are in agreement with studies from the cortex and the balanced model. It is therefore relevant to study the population activity in the spinal cord for traits from cortex...... (Buzsáki and Mizuseki, 2014). Roxin et al. (2011) detailed the firing rate distribution in networks in the balanced regime, and found it to be similar to a lognormal distribution and describing the data from the population studies very well. Our experimental observations and analysis are in agreement......In biological networks, millions of neurons organize themselves from microscopic noisy individuals to robust macroscopic entities. These entities are capable of producing higher functions like sensory processing, decision-making, and elaborate behavioral responses. Every aspect of these behaviors...

  4. Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease.

    Science.gov (United States)

    Palmisano, Ralf; Golfi, Panagiota; Heimann, Peter; Shaw, Christopher; Troakes, Claire; Schmitt-John, Thomas; Bartsch, Jörg W

    2011-03-07

    The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS. In motor neurons of homozygous symptomatic WR mice, a massive number of endosomal vesicles significantly enlarged (up to 3 μm in diameter) were subjected to ultrastructural analysis and immunohistochemistry for the endosome-specific small GTPase protein Rab7 and for amyloid precursor protein (APP). Enlarged vesicles were neither detected in heterozygous WR nor in transgenic SOD1(G93A) mice; in WR motor neurons, numerous APP/Rab7-positive vesicles were observed which were mostly LC3-negative, suggesting they are not autophagosomes. We conclude that endosomal APP/Rab7 staining reflects impaired vesicle trafficking in WR mouse motor neurons. Based on these findings human ALS tissues were analysed for APP in enlarged vesicles and were detected in spinal cord motor neurons in six out of fourteen sporadic ALS cases. These enlarged vesicles were not detected in any of the familial ALS cases. Thus our study provides the first evidence for wobbler-like aetiologies in human ALS and suggests that the genes encoding proteins involved in vesicle trafficking should be screened for pathogenic mutations.

  5. Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development.

    Directory of Open Access Journals (Sweden)

    Matthew J Fogarty

    Full Text Available Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E day 13 and birth (postnatal day 0. Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study. For respiratory-based motor neurons (hypoglossal and phrenic motor pools, we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic and muscle innervations (55% decrease. By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase and muscle innervations (99% increase; however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to

  6. Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development.

    Science.gov (United States)

    Fogarty, Matthew J; Smallcombe, Karen L; Yanagawa, Yuchio; Obata, Kunihiko; Bellingham, Mark C; Noakes, Peter G

    2013-01-01

    Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E) day 13 and birth (postnatal day 0). Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study). For respiratory-based motor neurons (hypoglossal and phrenic motor pools), we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic) and muscle innervations (55% decrease). By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase) and muscle innervations (99% increase); however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar) regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to that of

  7. Contributions of intrinsic motor neuron properties to the production of rhythmic motor output in the mammalian spinal cord

    DEFF Research Database (Denmark)

    Kiehn, O; Kjaerulff, O; Tresch, M C

    2000-01-01

    showing that the neonatal rat spinal cord can produce a stable motor rhythm in the absence of spike activity in premotor interneuronal networks. These coordinated motor neuron oscillations are dependent on NMDA-evoked pacemaker properties, which are synchronized across gap junctions. We discuss...... the functional relevance for such coordinated oscillations in immature and mature spinal motor systems.......Motor neurons are endowed with intrinsic and conditional membrane properties that may shape the final motor output. In the first half of this paper we present data on the contribution of I(h), a hyperpolarization-activated inward cation current, to phase-transition in motor neurons during rhythmic...

  8. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

    Science.gov (United States)

    Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

    2017-03-01

    The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

  9. Selected statins produce rapid spinal motor neuron loss in vitro

    Directory of Open Access Journals (Sweden)

    Murinson Beth B

    2012-06-01

    Full Text Available Abstract Background Hmg-CoA reductase inhibitors (statins are widely used to prevent disease associated with vascular disease and hyperlipidemia. Although side effects are uncommon, clinical observations suggest statin exposure may exacerbate neuromuscular diseases, including peripheral neuropathy and amyotrophic lateral sclerosis. Although some have postulated class-effects, prior studies of hepatocytes and myocytes indicate that the statins may exhibit differential effects. Studies of neuronal cells have been limited. Methods We examined the effects of statins on cultured neurons and Schwann cells. Cultured spinal motor neurons were grown on transwell inserts and assessed for viability using immunochemical staining for SMI-32. Cultured cortical neurons and Schwann cells were assessed using dynamic viability markers. Results 7 days of exposure to fluvastatin depleted spinal motor neurons in a dose-dependent manner with a KD of  Conclusions It is known from pharmacokinetic studies that daily treatment of young adults with fluvastatin can produce serum levels in the single micromolar range. We conclude that specific mechanisms may explain neuromuscular disease worsening with statins and further study is needed.

  10. Human endogenous retrovirus-K contributes to motor neuron disease.

    Science.gov (United States)

    Li, Wenxue; Lee, Myoung-Hwa; Henderson, Lisa; Tyagi, Richa; Bachani, Muzna; Steiner, Joseph; Campanac, Emilie; Hoffman, Dax A; von Geldern, Gloria; Johnson, Kory; Maric, Dragan; Morris, H Douglas; Lentz, Margaret; Pak, Katherine; Mammen, Andrew; Ostrow, Lyle; Rothstein, Jeffrey; Nath, Avindra

    2015-09-30

    The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  11. iPSC-derived Insights into Motor Neuron Disease and Inflammatory Neuropathies

    NARCIS (Netherlands)

    Härschnitz, O.

    2017-01-01

    The proper function of the motor circuit is essential for normal interaction as a human being with external cues. While the motor circuit consists of a variety of cell types, one of its core components is the motor neuron itself. Dysfunction of motor neurons is a hallmark of many neuromuscular

  12. Effectiveness of upper limb functional electrical stimulation after stroke for the improvement of activities of daily living and motor function: a systematic review and meta-analysis

    OpenAIRE

    Eraifej, John; Clark, William; France, Benjamin; Desando, Sebastian; Moore, David

    2017-01-01

    Background Stroke can lead to significant impairment of upper limb function which affects performance of activities of daily living (ADL). Functional electrical stimulation (FES) involves electrical stimulation of motor neurons such that muscle groups contract and create or augment a moment about a joint. Whilst lower limb FES was established in post-stroke rehabilitation, there is a lack of clarity on the effectiveness of upper limb FES. This systematic review aims to evaluate the effectiven...

  13. Decoding post-stroke motor function from structural brain imaging

    Directory of Open Access Journals (Sweden)

    Jane M. Rondina

    2016-01-01

    Full Text Available Clinical research based on neuroimaging data has benefited from machine learning methods, which have the ability to provide individualized predictions and to account for the interaction among units of information in the brain. Application of machine learning in structural imaging to investigate diseases that involve brain injury presents an additional challenge, especially in conditions like stroke, due to the high variability across patients regarding characteristics of the lesions. Extracting data from anatomical images in a way that translates brain damage information into features to be used as input to learning algorithms is still an open question. One of the most common approaches to capture regional information from brain injury is to obtain the lesion load per region (i.e. the proportion of voxels in anatomical structures that are considered to be damaged. However, no systematic evaluation has yet been performed to compare this approach with using patterns of voxels (i.e. considering each voxel as a single feature. In this paper we compared both approaches applying Gaussian Process Regression to decode motor scores in 50 chronic stroke patients based solely on data derived from structural MRI. For both approaches we compared different ways to delimit anatomical areas: regions of interest from an anatomical atlas, the corticospinal tract, a mask obtained from fMRI analysis with a motor task in healthy controls and regions selected using lesion-symptom mapping. Our analysis showed that extracting features through patterns of voxels that represent lesion probability produced better results than quantifying the lesion load per region. In particular, from the different ways to delimit anatomical areas compared, the best performance was obtained with a combination of a range of cortical and subcortical motor areas as well as the corticospinal tract. These results will inform the appropriate methodology for predicting long term motor outcomes

  14. Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Statland, Jeffrey M; Barohn, Richard J; McVey, April L; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Physical Activity, Ambulation, and Motor Impairment Late after Stroke

    Directory of Open Access Journals (Sweden)

    Anna Danielsson

    2012-01-01

    Full Text Available Objective. To assess walking capacity and physical activity using clinical measures and to explore their relationships with motor impairment late after stroke. Subjects. A nonrandomised sample of 22 men and 9 women with a mean age of 60 years, 7–10 years after stroke. Methods. Fugl-Meyer Assessment, maximum walking speed, 6 min walk test, perceived exertion, and heart rate were measured, and the Physiological Cost Index was calculated. Physical activity was reported using The Physical Activity Scale for the Elderly. Results. Mean (SD 6 min walking distance was 352 (±136 m, and Physiological Cost Index was 0.60 (±0.41. Self-reported physical activity was 70% of the reference. Motor impairment correlated with walking capacity but not with the physical activity level. Conclusion. It may be essential to enhance physical activity even late after stroke since in fairly young subjects both walking capacity and the physical activity level were lower than the reference.

  16. Brain-wide neuronal dynamics during motor adaptation in zebrafish.

    Science.gov (United States)

    Ahrens, Misha B; Li, Jennifer M; Orger, Michael B; Robson, Drew N; Schier, Alexander F; Engert, Florian; Portugues, Ruben

    2012-05-09

    A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.

  17. Effect of action observation therapy on daily activities and motor recovery in stroke patients

    Directory of Open Access Journals (Sweden)

    Mei-Hong Zhu

    2015-09-01

    Conclusion: Action observation therapy significantly improves upper extremity motor function and performance of activities of daily living, and alleviates upper limb spasticity in patients with stroke.

  18. Selective vulnerability of spinal and cortical motor neuron subpopulations in delta7 SMA mice.

    Science.gov (United States)

    d'Errico, Paolo; Boido, Marina; Piras, Antonio; Valsecchi, Valeria; De Amicis, Elena; Locatelli, Denise; Capra, Silvia; Vagni, Francesco; Vercelli, Alessandro; Battaglia, Giorgio

    2013-01-01

    Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.

  19. Applicability of a motor rehabilitation system in stroke victims

    Directory of Open Access Journals (Sweden)

    Maíra Izzadora Souza Carneiro

    Full Text Available Abstract Introduction: The recovery of stroke patients is long and boring due to the repetitive nature of the exercises used and the length of treatment. Thus, we started using virtual reality as an alternative and, because of its advantages, health professionals are adapting video games for physical therapy. However, there are some limitations, such as the fact that games are designed for entertainment and not for therapeutic purposes. Objective: In order to mitigate gaps in assistive devices for physical therapy, this study describes the development and applicability of a computer support system for motor rehabilitation - Ikapp - in stroke victims. Methods: Twenty-seven stroke patients filled out a socioeconomic questionnaire, tested Ikapp during five minutes and answered a usability and satisfaction questionnaire about handling the tool. The chi-square test was used to analyze any association between sociodemographic factors and the features of the system. Results: The Ikapp system can be an excellent device to assist neurological rehabilitation of stroke patients, as participants questionnaires showed that 85.2% were satisfied in regard to motivation and inclusion of Ikapp in physiotherapy and 77.8% relative to ease of interaction with the tool. Conclusion: The Ikapp system proved to be an easy-to-use and accessible computer support system for patients with functional limitations.

  20. Effect of motor relearning programme on motor function recovery of acute stroke patients with hemiplegia

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    Min GUAN

    2017-03-01

    Full Text Available Objective To explore the effect of motor relearning programme (MRP on motor function recovery of patients with hemiplegia after acute stroke.  Methods A total of 64 hemiplegic patients with acute stroke (duration ≤ 14 d were randomly divided into 2 groups: control group (N = 32 and observation group (N = 32. Control group received routine drug therapy and conventional rehabilitation training, and observation group was treated by routine therapy and MRP training. Fugl-Meyer Assessment Scale - Balance (FMA - Balance, Modified Rivermead Mobility Index (MRMI and modified Barthel Index (mBI were used to assess the motor function of patients in both groups before and after treatment.  Results All patients successfully completed the rehabilitation training without severe adverse events. A few patients felt fatigue occasionally after training and recovered after rest. Compared to before treatment, the FMA-Balance score (P = 0.000, MRMI score (P = 0.000 and mBI score (P = 0.000 after treatment in both groups were significantly increased. Compared to control group, the FMA-Balance score (P = 0.031, MRMI score (P = 0.013 and mBI score (P = 0.049 after treatment in observation group were significantly increased.  Conclusions MRP training in the early stage of stroke is beneficial to the recovery of motor function of patients. DOI: 10.3969/j.issn.1672-6731.2017.03.007

  1. Association Between Brain-Derived Neurotrophic Factor Genotype and Upper Extremity Motor Outcome After Stroke.

    Science.gov (United States)

    Chang, Won Hyuk; Park, Eunhee; Lee, Jungsoo; Lee, Ahee; Kim, Yun-Hee

    2017-06-01

    The identification of intrinsic factors for predicting upper extremity motor outcome could aid the design of individualized treatment plans in stroke rehabilitation. The aim of this study was to identify prognostic factors, including intrinsic genetic factors, for upper extremity motor outcome in patients with subacute stroke. A total of 97 patients with subacute stroke were enrolled. Upper limb motor impairment was scored according to the upper limb of Fugl-Meyer assessment score at 3 months after stroke. The prediction of upper extremity motor outcome at 3 months was modeled using various factors that could potentially influence this impairment, including patient characteristics, baseline upper extremity motor impairment, functional and structural integrity of the corticospinal tract, and brain-derived neurotrophic factor genotype. Multivariate ordinal logistic regression models were used to identify the significance of each factor. The independent predictors of motor outcome at 3 months were baseline upper extremity motor impairment, age, stroke type, and corticospinal tract functional integrity in all stroke patients. However, in the group with severe motor impairment at baseline (upper limb score of Fugl-Meyer assessment stroke. Brain-derived neurotrophic factor genotype may be a potentially useful predictor of upper extremity motor outcome in patients with subacute stroke with severe baseline motor involvement. © 2017 American Heart Association, Inc.

  2. Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

    Science.gov (United States)

    Nash, L A; Burns, J K; Chardon, J Warman; Kothary, R; Parks, R J

    2016-01-01

    Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Fine finger motor skill training with exoskeleton robotic hand in chronic stroke: stroke rehabilitation.

    Science.gov (United States)

    Ockenfeld, Corinna; Tong, Raymond K Y; Susanto, Evan A; Ho, Sze-Kit; Hu, Xiao-ling

    2013-06-01

    Background and Purpose. Stroke survivors often show a limited recovery in the hand function to perform delicate motions, such as full hand grasping, finger pinching and individual finger movement. The purpose of this study is to describe the implementation of an exoskeleton robotic hand together with fine finger motor skill training on 2 chronic stroke patients. Case Descriptions. Two post-stroke patients participated in a 20-session training program by integrating 10 minutes physical therapy, 20 minutes robotic hand training and 15 minutes functional training tasks with delicate objects(card, pen and coin). These two patients (A and B) had cerebrovascular accident at 6 months and 11 months respectively when enrolled in this study. Outcomes. The results showed that both patients had improvements in Fugl-Meyer assessment (FM), Action Research Arm Test (ARAT). Patients had better isolation of the individual finger flexion and extension based on the reduced muscle co-contraction from the electromyographic(EMG) signals and finger extension force after 20 sessions of training. Discussion. This preliminary study showed that by focusing on the fine finger motor skills together with the exoskeleton robotic hand, it could improve the motor recovery of the upper extremity in the fingers and hand function, which were showed in the ARAT. Future randomized controlled trials are needed to evaluate the clinical effectiveness.

  4. Apoptosis of Limb Innervating Motor Neurons and Erosion of Motor Pool Identity Upon Lineage Specific Dicer Inactivation

    Science.gov (United States)

    Chen, Jun-An; Wichterle, Hynek

    2012-01-01

    Diversification of mammalian spinal motor neurons into hundreds of subtypes is critical for the maintenance of body posture and coordination of complex movements. Motor neuron differentiation is controlled by extrinsic signals that regulate intrinsic genetic programs specifying and consolidating motor neuron subtype identity. While transcription factors have been recognized as principal regulators of the intrinsic program, the role of posttranscriptional regulations has not been systematically tested. MicroRNAs produced by Dicer mediated cleavage of RNA hairpins contribute to gene regulation by posttranscriptional silencing. Here we used Olig2-cre conditional deletion of Dicer gene in motor neuron progenitors to examine effects of miRNA biogenesis disruption on postmitotic spinal motor neurons. We report that despite the initial increase in the number of motor neuron progenitors, disruption of Dicer function results in a loss of many limb- and sympathetic ganglia-innervating spinal motor neurons. Furthermore, it leads to defects in motor pool identity specification. Thus, our results indicate that miRNAs are an integral part of the genetic program controlling motor neuron survival and acquisition of subtype specific properties. PMID:22629237

  5. Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

    Directory of Open Access Journals (Sweden)

    Barış Genç

    Full Text Available Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

  6. Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

    Science.gov (United States)

    Genç, Barış; Lagrimas, Amiko Krisa Bunag; Kuru, Pınar; Hess, Robert; Tu, Michael William; Menichella, Daniela Maria; Miller, Richard J; Paller, Amy S; Özdinler, P Hande

    2015-01-01

    Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

  7. Neurotrophic requirements of human motor neurons defined using amplified and purified stem cell-derived cultures.

    Directory of Open Access Journals (Sweden)

    Nuno Jorge Lamas

    Full Text Available Human motor neurons derived from embryonic and induced pluripotent stem cells (hESCs and hiPSCs are a potentially important tool for studying motor neuron survival and pathological cell death. However, their basic survival requirements remain poorly characterized. Here, we sought to optimize a robust survival assay and characterize their response to different neurotrophic factors. First, to increase motor neuron yield, we screened a small-molecule collection and found that the Rho-associated kinase (ROCK inhibitor Y-27632 enhances motor neuron progenitor proliferation up to 4-fold in hESC and hiPSC cultures. Next, we FACS-purified motor neurons expressing the Hb9::GFP reporter from Y-27632-amplified embryoid bodies and cultured them in the presence of mitotic inhibitors to eliminate dividing progenitors. Survival of these purified motor neurons in the absence of any other cell type was strongly dependent on neurotrophic support. GDNF, BDNF and CNTF all showed potent survival effects (EC(50 1-2 pM. The number of surviving motor neurons was further enhanced in the presence of forskolin and IBMX, agents that increase endogenous cAMP levels. As a demonstration of the ability of the assay to detect novel neurotrophic agents, Y-27632 itself was found to support human motor neuron survival. Thus, purified human stem cell-derived motor neurons show survival requirements similar to those of primary rodent motor neurons and can be used for rigorous cell-based screening.

  8. Examining Differences in Patterns of Sensory and Motor Recovery After Stroke With Robotics.

    Science.gov (United States)

    Semrau, Jennifer A; Herter, Troy M; Scott, Stephen H; Dukelow, Sean P

    2015-12-01

    Developing a better understanding of the trajectory and timing of stroke recovery is critical for developing patient-centered rehabilitation approaches. Here, we quantified proprioceptive and motor deficits using robotic technology during the first 6 months post stroke to characterize timing and patterns in recovery. We also make comparisons of robotic assessments to traditional clinical measures. One hundred sixteen subjects with unilateral stroke were studied at 4 time points: 1, 6, 12, and 26 weeks post stroke. Subjects performed robotic assessments of proprioceptive (position sense and kinesthesia) and motor function (unilateral reaching task and bimanual object hit task), as well as several clinical measures (Functional Independence Measure, Purdue Pegboard, and Chedoke-McMaster Stroke Assessment). One week post stroke, many subjects displayed proprioceptive (48% position sense and 68% kinesthesia) and motor impairments (80% unilateral reaching and 85% bilateral movement). Interindividual recovery on robotic measures was highly variable. However, we characterized recovery as early (normal by 6 weeks post stroke), late (normal by 26 weeks post stroke), or incomplete (impaired at 26 weeks post stroke). Proprioceptive and motor recovery often followed different timelines. Across all time points, robotic measures were correlated with clinical measures. These results highlight the need for more sensitive, targeted identification of sensory and motor deficits to optimize rehabilitation after stroke. Furthermore, the trajectory of recovery for some individuals with mild to moderate stroke may be much longer than previously considered. © 2015 American Heart Association, Inc.

  9. Long-Stroke Nanopositioning Stage Driven by Piezoelectric Motor

    Directory of Open Access Journals (Sweden)

    Yong Wang

    2014-01-01

    Full Text Available This paper reported a biaxial nanopositioning stage single-driven by piezoelectric motor. The employed piezoelectric motor can perform two different driving modes, namely, AC drive mode to drive in long-stroke and at high-speed and DC scanning mode with the high-resolution of several nanometers, which satisfies the requirements of both long-stroke and nanoresolution. To compensate for the effects of the variable friction force and some unpredictable disturbances, a novel backward error compensation (BEC positioning control method integrated of the two driving modes and a double closed-loop PID controller system are proposed to obtain a high-accuracy positional motion. The experiment results demonstrate that the nanopositioning stage with large travel range of 300 mm × 300 mm has a fine speed characteristic and resolution is 5 nm. In the experiments of different travels up to 15 mm, calibrated by a commercial laser vibrometer, the positioning accuracy is proved within 55 nm in x-axis and 40 nm in y-axis with standard deviation less than 40 nm in x-axis and 30 nm in y-axis and the final position locking can be limited to 10 nm, meeting the requirements of micromanipulation technology.

  10. Histone deacetylases and their role in motor neuron degeneration

    Directory of Open Access Journals (Sweden)

    Rafael eLazo-Gómez

    2013-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases and deacetylases, respectively whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins and their effectors.

  11. Contributions of intrinsic motor neuron properties to the production of rhythmic motor output in the mammalian spinal cord

    DEFF Research Database (Denmark)

    Kiehn, O; Kjaerulff, O; Tresch, M C

    2000-01-01

    Motor neurons are endowed with intrinsic and conditional membrane properties that may shape the final motor output. In the first half of this paper we present data on the contribution of I(h), a hyperpolarization-activated inward cation current, to phase-transition in motor neurons during rhythmic...... firing. Motor neurons were recorded intracellularly during locomotion induced with a mixture of N-methyl-D-aspartate (NMDA) and serotonin, after pharmacological blockade of I(h). I(h) was then replaced by using dynamic clamp, a computer program that allows artificial conductances to be inserted into real...... neurons. I(h) was simulated with biophysical parameters determined in voltage clamp experiments. The data showed that electronic replacement of the native I(h) caused a depolarization of the average membrane potential, a phase-advance of the locomotor drive potential, and increased motor neuron spiking...

  12. Resting-state interhemispheric motor connectivity and white matter integrity correlate with motor impairment in chronic stroke

    Directory of Open Access Journals (Sweden)

    Joyce L Chen

    2013-11-01

    Full Text Available Functional and structural reorganization in the brain occurs after stroke. The ability to predict motor outcomes may depend on patterns of brain functional and structural connectivity. We tested the hypothesis that alterations in motor transcallosal and corticospinal connections correlate with motor impairment in patients with chronic stroke. Eleven ischemic stroke patients underwent the Upper Extremity Fugl Meyer assessment, resting state functional magnetic resonance imaging, and diffusion tensor imaging. Twelve healthy control subjects underwent diffusion tensor imaging. We assessed the temporal coupling in neural activity between interhemispheric motor cortex, and white matter integrity by means of fractional anisotropy, in the transcallosal motor fibers and corticospinal tract. Partial correlation analyses were performed to determine whether these connectivity measures correlate with Upper Extremity Fugl Meyer scores. Patients compared to controls had reduced fractional anisotropy in common voxels of transcallosal motor and ipsilesional corticospinal fibers. Within the patient group those with higher interhemispheric motor cortex connectivity and higher fractional anisotropy in the transcallosal motor fibers were less impaired. The results show that markers of functional and structural motor cortex connectivity correlate with motor impairment in the chronic stage of stroke.

  13. Increased motor neuron resilience by small molecule compounds that regulate IGF-II expression.

    Science.gov (United States)

    Osborn, Teresia M; Beagan, Jonathan; Isacson, Ole

    2018-02-01

    The selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is evident by sparing of a few subpopulations during this fast progressing and debilitating degenerative disease. By studying the gene expression profile of resilient vs. vulnerable motor neuron populations we can gain insight in what biomolecules and pathways may contribute to the resilience and vulnerability. Several genes have been found to be differentially expressed in the vulnerable motor neurons of the cervical spinal cord as compared to the spared motor neurons in CNIII/IV. One gene that is differentially expressed and present at higher levels in less vulnerable motor neurons is insulin-like growth factor II (IGF-II). The motor neuron protective effect of IGF-II has been demonstrated both in vitro and in SOD1 transgenic mice. Here, we have screened a library of small molecule compounds and identified inducers of IGF-II mRNA and protein expression. Several identified compounds significantly protected motor neurons from glutamate excitotoxicity in vitro. One of the compounds, vardenafil, resulted in a complete motor neuron protection, an effect that was reversed by blocking receptors of IGF-II. When administered to naïve rats vardenafil was present in the cerebrospinal fluid and increased IGF-II mRNA expression in the spinal cord. When administered to SOD1 transgenic mice, there was a significant delay in motor symptom onset and prolonged survival. Vardenafil also increased IGF-II mRNA and protein levels in motor neurons derived from healthy subject and ALS patient iPSCs, activated a human IGF-II promoter and improved survival of ALS-patient derived motor neurons in culture. Our findings suggest that modulation of genes differentially expressed in vulnerable and resilient motor neurons may be a useful therapeutic approach for motor neuron disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Can molecular motors drive distance measurements in injured neurons?

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    Naaman Kam

    2009-08-01

    Full Text Available Injury to nerve axons induces diverse responses in neuronal cell bodies, some of which are influenced by the distance from the site of injury. This suggests that neurons have the capacity to estimate the distance of the injury site from their cell body. Recent work has shown that the molecular motor dynein transports importin-mediated retrograde signaling complexes from axonal lesion sites to cell bodies, raising the question whether dynein-based mechanisms enable axonal distance estimations in injured neurons? We used computer simulations to examine mechanisms that may provide nerve cells with dynein-dependent distance assessment capabilities. A multiple-signals model was postulated based on the time delay between the arrival of two or more signals produced at the site of injury-a rapid signal carried by action potentials or similar mechanisms and slower signals carried by dynein. The time delay between the arrivals of these two types of signals should reflect the distance traversed, and simulations of this model show that it can indeed provide a basis for distance measurements in the context of nerve injuries. The analyses indicate that the suggested mechanism can allow nerve cells to discriminate between distances differing by 10% or more of their total axon length, and suggest that dynein-based retrograde signaling in neurons can be utilized for this purpose over different scales of nerves and organisms. Moreover, such a mechanism might also function in synapse to nucleus signaling in uninjured neurons. This could potentially allow a neuron to dynamically sense the relative lengths of its processes on an ongoing basis, enabling appropriate metabolic output from cell body to processes.

  15. Can molecular motors drive distance measurements in injured neurons?

    Science.gov (United States)

    Kam, Naaman; Pilpel, Yitzhak; Fainzilber, Mike

    2009-08-01

    Injury to nerve axons induces diverse responses in neuronal cell bodies, some of which are influenced by the distance from the site of injury. This suggests that neurons have the capacity to estimate the distance of the injury site from their cell body. Recent work has shown that the molecular motor dynein transports importin-mediated retrograde signaling complexes from axonal lesion sites to cell bodies, raising the question whether dynein-based mechanisms enable axonal distance estimations in injured neurons? We used computer simulations to examine mechanisms that may provide nerve cells with dynein-dependent distance assessment capabilities. A multiple-signals model was postulated based on the time delay between the arrival of two or more signals produced at the site of injury-a rapid signal carried by action potentials or similar mechanisms and slower signals carried by dynein. The time delay between the arrivals of these two types of signals should reflect the distance traversed, and simulations of this model show that it can indeed provide a basis for distance measurements in the context of nerve injuries. The analyses indicate that the suggested mechanism can allow nerve cells to discriminate between distances differing by 10% or more of their total axon length, and suggest that dynein-based retrograde signaling in neurons can be utilized for this purpose over different scales of nerves and organisms. Moreover, such a mechanism might also function in synapse to nucleus signaling in uninjured neurons. This could potentially allow a neuron to dynamically sense the relative lengths of its processes on an ongoing basis, enabling appropriate metabolic output from cell body to processes.

  16. dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration.

    Science.gov (United States)

    Ikenaka, Kensuke; Kawai, Kaori; Katsuno, Masahisa; Huang, Zhe; Jiang, Yue-Mei; Iguchi, Yohei; Kobayashi, Kyogo; Kimata, Tsubasa; Waza, Masahiro; Tanaka, Fumiaki; Mori, Ikue; Sobue, Gen

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.

  17. dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration.

    Directory of Open Access Journals (Sweden)

    Kensuke Ikenaka

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.

  18. Motor impairment and neuronal damage following hypothermia in tropical amphibians.

    Science.gov (United States)

    Daló, Nelson L; Bracho, Gustavo A; Piña-Crespo, Juan C

    2007-02-01

    Although the induction of mild to moderate cerebral hypothermia in mammals can have neuroprotective activity, some deleterious effects have been described when inducing deep hypothermia during cooling of the brain. In the spinal cord, rapid deep cooling can induce seizure activity accompanied by release of the excitatory neurotransmitters, glutamate and aspartate. We used cold-sensitive tropical amphibians as a model to determine (a) the critical temperature inside the central nervous system necessary to induce seizures during rapid cooling; (b) the survival rate during slow deep cooling of the whole animal; and (c) whether deep cooling can cause neuronal cell damage. Seizures induced by deep rapid (or=30 min) deep cooling of the whole animal (12 h at 2-3 degrees C), around 70% of animals died. Spinal reflexes were enhanced when temperatures within the spinal cord reached between 9.0 degrees C and 11.6 degrees C. A fivefold increase in blood glucose level was observed during slow deep cooling. Recovery after slow deep cooling was accompanied by motor impairment and the main histological findings were condensation of the cytoplasm and nuclear pyknosis. Severe neuronal cell damage was characterized by swelling, vacuolated cytoplasm with distended neuronal bodies. These results indicate that deep cooling can easily induce neuronal cell damage in the central nervous system of cold-sensitive animals. They also warn us to the potential sequels associated with the use of deep brain cooling as a neuroprotective strategy.

  19. Patterns of symptom development in patients with motor neuron disease.

    Science.gov (United States)

    Walhout, Renée; Verstraete, Esther; van den Heuvel, Martijn P; Veldink, Jan H; van den Berg, Leonard H

    2018-02-01

    To investigate whether symptom development in motor neuron disease (MND) is a random or organized process. Six hundred patients with amyotrophic lateral sclerosis (ALS), upper motor neuron (UMN) or lower motor neuron (LMN) phenotypes were invited for a questionnaire concerning symptom development. A binomial test was used to examine distribution of symptoms from site of onset. Development of symptoms over time was evaluated by Kaplan-Meier analysis. There were 470 respondents (ALS = 254; LMN = 100; UMN = 116). Subsequent symptoms were more often in the contralateral limb following unilateral limb onset (ALS: arms p = 1.05 × 10 -8 , legs p < 2.86 × 10 -15 ; LMN phenotype: arms p = 6.74 × 10 -9 , legs p = 6.26 × 10 -6 ; UMN phenotype: legs p = 4.07 × 10 -14 ). In patients with limb onset, symptoms occurred significantly faster in the contralateral limb, followed by the other limbs and lastly by the bulbar region. Patterns of non-contiguous symptom development were also reported: leg symptoms followed bulbar onset in 30%, and bulbar symptoms followed leg onset in 11% of ALS patients. Preferred spread of symptoms from one limb to the contralateral limb, and to adjacent sites appears to be a characteristic of MND phenotypes, suggesting that symptom spread is organized, possibly involving axonal connectivity. Non-contiguous symptom development, however, is not uncommon, and may involve other factors.

  20. Differential activity patterns of putaminal neurons with inputs from the primary motor cortex and supplementary motor area in behaving monkeys.

    Science.gov (United States)

    Takara, Sayuki; Hatanaka, Nobuhiko; Takada, Masahiko; Nambu, Atsushi

    2011-09-01

    Activity patterns of projection neurons in the putamen were investigated in behaving monkeys. Stimulating electrodes were implanted chronically into the proximal (MI(proximal)) and distal (MI(distal)) forelimb regions of the primary motor cortex (MI) and the forelimb region of the supplementary motor area (SMA). Cortical inputs to putaminal neurons were identified by excitatory orthodromic responses to stimulation of these motor cortices. Then, neuronal activity was recorded during the performance of a goal-directed reaching task with delay. Putaminal neurons with inputs from the MI and SMA showed different activity patterns, i.e., movement- and delay-related activity, during task performance. MI-recipient neurons increased activity in response to arm-reach movements, whereas SMA-recipient neurons increased activity during delay periods, as well as during movements. The activity pattern of MI + SMA-recipient neurons was of an intermediate type between those of MI- and SMA-recipient neurons. Approximately one-half of MI(proximal)-, SMA-, and MI + SMA-recipient neurons changed activities before the onset of movements, whereas a smaller number of MI(distal)- and MI(proximal + distal)-recipient neurons did. Movement-related activity of MI-recipient neurons was modulated by target directions, whereas SMA- and MI + SMA-recipient neurons had a lower directional selectivity. MI-recipient neurons were located mainly in the ventrolateral part of the caudal aspect of the putamen, whereas SMA-recipient neurons were located in the dorsomedial part. MI + SMA-recipient neurons were found in between. The present results suggest that a subpopulation of putaminal neurons displays specific activity patterns depending on motor cortical inputs. Each subpopulation receives convergent or nonconvergent inputs from the MI and SMA, retains specific motor information, and sends it to the globus pallidus and the substantia nigra through the direct and indirect pathways of the basal ganglia.

  1. Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis.

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    Yazhou Li

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1, facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4 is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells and in vivo (SOD1 G93A mutant mice models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.

  2. MicroRNA-128 governs neuronal excitability and motor behavior in mice

    DEFF Research Database (Denmark)

    Tan, Chan Lek; Plotkin, Joshua L.; Venø, Morten Trillingsgaard

    2013-01-01

    The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks...... and excitability. miR-128 governs motor activity by suppressing the expression of various ion channels and signaling components of the extracellular signal-regulated kinase ERK2 network that regulate neuronal excitability. In mice, a reduction of miR-128 expression in postnatal neurons causes increased motor...... activity and fatal epilepsy. Overexpression of miR-128 attenuates neuronal responsiveness, suppresses motor activity, and alleviates motor abnormalities associated with Parkinson's-like disease and seizures in mice. These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy...

  3. Neuromuscular ultrasound in polyneuropathies and motor neuron disease.

    Science.gov (United States)

    Hobson-Webb, Lisa D

    2013-06-01

    Current standards for diagnosing polyneuropathies (PN) and motor neuron disease (MND) sometimes lack early sensitivity and result in delayed diagnosis and treatment. Neuromuscular ultrasound (NMUS), already established in the diagnosis of entrapment neuropathies, may offer another means of diagnosis and monitoring response to therapy. This review of current evidence discusses diffuse nerve hypertrophy in hereditary demyelinating neuropathies, multifocal nerve enlargement in acquired demyelinating PN and the lack of readily apparent structural change in axonal neuropathies. NMUS detection of fasciculations and muscular change in MND is also reviewed, along with the need for further research to better define the role of nerve imaging in patients with PN. Copyright © 2013 Wiley Periodicals, Inc.

  4. Transcranial magnetic stimulation in lower motor neuron diseases.

    Science.gov (United States)

    Attarian, S; Azulay, J-Ph; Lardillier, D; Verschueren, A; Pouget, J

    2005-01-01

    To study the diagnostic value of transcranial magnetic stimulation (TMS) in a group of patients with lower motor neuron disease (LMND). Among LMND, several chronic immune mediate motor neuropathies may simulate amyotrophic lateral sclerosis (ALS). Forty patients with LMND were included TMS was performed at the first visit. The patients were seen prospectively every 3 months for a period of 1-4 years. Three different groups were distinguished at the end of follow-up: (1) ALS group with 7 patients, (2) Pure motor neuropathy with 14 patients and (3) Other LMND including 12 patients with hereditary spinal amyotrophy, 3 patients with Kennedy's disease and 4 patients with post-poliomyelitis. On the basis of the results of TMS variables, 6 out of 7 ALS patients had abnormality of silent period (SP) associated or not with abnormality of excitatory threshold or amplitude ratio. Patients with pure motor neuropathy had normal SP and amplitude ratio. Four out of 14 patients had increased central motor conduction time (CMCT), one had increased CMCT and excitatory threshold, and one patient had a slightly increased excitatory threshold. Considering the abnormality of TMS variables in the groups, SP, excitatory threshold, and amplitude ratio were chosen in a post-hoc attempt to select variables yielding high sensitivity and specificity. The overall sensitivity of TMS for diagnosis of ALS among LMND was 85.7%, its specificity was 93.9%. When only the abnormality of SP was taken into account, the sensitivity was unchanged. But the specificity was improved to 100%. TMS helped to distinguish suspected ALS from pure motor neuropathy.

  5. Multimodal structural MRI in the diagnosis of motor neuron diseases

    Directory of Open Access Journals (Sweden)

    Pilar M. Ferraro

    2017-01-01

    Full Text Available This prospective study developed an MRI-based method for identification of individual motor neuron disease (MND patients and test its accuracy at the individual patient level in an independent sample compared with mimic disorders. 123 patients with amyotrophic lateral sclerosis (ALS, 44 patients with predominantly upper motor neuron disease (PUMN, 20 patients with ALS-mimic disorders, and 78 healthy controls were studied. The diagnostic accuracy of precentral cortical thickness and diffusion tensor (DT MRI metrics of corticospinal and motor callosal tracts were assessed in a training cohort and externally proved in a validation cohort using a random forest analysis. In the training set, precentral cortical thickness showed 0.86 and 0.89 accuracy in differentiating ALS and PUMN patients from controls, while DT MRI distinguished the two groups from controls with 0.78 and 0.92 accuracy. In ALS vs controls, the combination of cortical thickness and DT MRI metrics (combined model improved the classification pattern (0.91 accuracy. In the validation cohort, the best accuracy was reached by DT MRI (0.87 and 0.95 accuracy in ALS and PUMN vs mimic disorders. The combined model distinguished ALS and PUMN patients from mimic syndromes with 0.87 and 0.94 accuracy. A multimodal MRI approach that incorporates motor cortical and white matter alterations yields statistically significant improvement in accuracy over using each modality separately in the individual MND patient classification. DT MRI represents the most powerful tool to distinguish MND from mimic disorders.

  6. Nonmotor symptoms in patients suffering from motor neuron diseases

    Directory of Open Access Journals (Sweden)

    Rene Günther

    2016-07-01

    Full Text Available Background: The recently postulated disease spreading hypothesis has gained much attention, especially for Parkinson’s disease (PD. The various nonmotor symptoms (NMS in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND is primarily known as a group of diseases with a selective loss of motor function. Recent evidence, however, suggests disease spreading into nonmotor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.Methods: We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric and sleep complaints (NMSQuest which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.Results: In total, MND patients reported significantly higher NMS scores (median: 7 points in comparison to controls (median: 4 points. Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.Conclusions: NMS in MND patients seemed to increase with disease progression which would fit with the recently postulated disease spreading hypothesis. The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

  7. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis*

    Science.gov (United States)

    Chen, Liuji; Hambright, William Sealy; Na, Ren; Ran, Qitao

    2015-01-01

    Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo. PMID:26400084

  8. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.

    Science.gov (United States)

    Chen, Liuji; Hambright, William Sealy; Na, Ren; Ran, Qitao

    2015-11-20

    Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Motor and Visuospatial Attention and Motor Planning After Stroke: Considerations for the Rehabilitation of Standing Balance and Gait

    Science.gov (United States)

    Peters, Sue; Handy, Todd C.; Lakhani, Bimal; Boyd, Lara A.

    2015-01-01

    Attention and planning can be altered by stroke, which can influence motor performance. Although the influence of these factors on recovery from stroke has been explored for the upper extremity (UE), their impact on balance and gait are unknown. This perspective article presents evidence that altered motor and visuospatial attention influence motor planning of voluntary goal-directed movements poststroke, potentially affecting balance and gait. Additionally, specific strategies for rehabilitation of balance and gait poststroke in the presence of these factors are discussed. Visuospatial attention selects relevant sensory information and supports the preparation of responses to this information. Motor attentional impairments may produce difficulty with selecting appropriate motor feedback, potentially contributing to falls. An original theoretical model is presented for a network of brain regions supporting motor and visuospatial attention, as well as motor planning of voluntary movements. Stroke may influence this functional network both locally and distally, interfering with input or output of the anatomical or functional regions involved and affecting voluntary movements. Although there is limited research directly examining leg function, evidence suggests alterations in motor and visuospatial attention influence motor planning and have a direct impact on performance of gait and balance. This model warrants testing comparing healthy adults with individuals with stroke. PMID:25929533

  10. Fishing for causes and cures of motor neuron disorders

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    Shunmoogum A. Patten

    2014-07-01

    Full Text Available Motor neuron disorders (MNDs are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA, amyotrophic lateral sclerosis (ALS and hereditary spastic paraplegia (HSP. These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

  11. Interactive Bio-feedback Therapy Using Hybrid Assistive Limbs for Motor Recovery after Stroke: Current Practice and Future Perspectives.

    Science.gov (United States)

    Morishita, Takashi; Inoue, Tooru

    2016-10-15

    Interactive bio-feedback (iBF) was initially developed for the rehabilitation of motor function in patients with neurological disorders, and subsequently yielded the development of the hybrid assistive limb (HAL). Here, we provide a review of the theory underlying HAL treatment as well as our clinical experience and recommendations for future clinical studies using HAL in acute stroke patients. We performed a PubMed-based literature search, a retrospective data review of our acute stroke case series, and included a sample case report of our findings. Given past animal studies and functional imaging results, iBF therapy using the HAL in the acute phase of stroke seems an appropriate approach for preventing learned non-use and interhemispheric excitation imbalances. iBF therapy may furthermore promote appropriate neuronal network reorganization. Based on experiences in our stroke center, HAL rehabilitation is a safe and effective treatment modality for recovering motor impairments after acute stroke, and allows the design of tailored rehabilitation programs for individual patients. iBF therapy through the HAL system seems to be an effective and promising approach to stroke rehabilitation; however, the superiority of this treatment to conventional rehabilitation remains unclear. Further clinical studies are warranted. Additionally, the formation of a patient registry will permit a meta-analysis of HAL cases and address the problems associated with a controlled trial (e.g., the heterogeneity of an acute stroke cohort). The development of robotic engineering will improve the efficacy of HAL rehabilitation and has the potential to standardize patient rehabilitation practice.

  12. Respiratory function after selective respiratory motor neuron death from intrapleural CTB-saporin injections.

    Science.gov (United States)

    Nichols, Nicole L; Vinit, Stéphane; Bauernschmidt, Lorene; Mitchell, Gordon S

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, paralysis and death by ventilatory failure. In rodent ALS models: 1) breathing capacity is preserved until late in disease progression despite major respiratory motor neuron death, suggesting unknown forms of compensatory respiratory plasticity; and 2) spinal microglia become activated in association with motor neuron cell death. Here, we report a novel experimental model to study the impact of respiratory motor neuron death on compensatory responses without many complications attendant to spontaneous motor neuron disease. In specific, we used intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) to selectively kill motor neurons with access to the pleural space. Motor neuron survival, CD11b labeling (microglia), ventilatory capacity and phrenic motor output were assessed in rats 3-28days after intrapleural injections of: 1) CTB-SAP (25 and 50μg), or 2) unconjugated CTB and SAP (i.e. control; (CTB+SAP). CTB-SAP elicited dose-dependent phrenic and intercostal motor neuron death; 7days post-25μg CTB-SAP, motor neuron survival approximated that in end-stage ALS rats (phrenic: 36±7%; intercostal: 56±10% of controls; n=9; pmotor nucleus, indicating microglial activation; 2) decreased breathing during maximal chemoreceptor stimulation; and 3) diminished phrenic motor output in anesthetized rats (7days post-25μg, 0.3±0.07V; CTB+SAP: 1.5±0.3; n=9; pmotor neuron death and provides an opportunity to study compensation for respiratory motor neuron loss. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Patient-reported measures provide unique insights into motor function after stroke.

    Science.gov (United States)

    Stewart, Jill Campbell; Cramer, Steven C

    2013-04-01

    Patient-reported outcome measures have been found useful in many disciplines but have received limited evaluation after stroke. The current study investigated the relationship that patient-reported measures have with standard impairment and disability scales after stroke. Patients with motor deficits after stroke were scored on standard assessments including the National Institutes of Health Stroke Scale, modified Rankin Scale, and Fugl-Meyer motor scale, and on 2 patient-reported measures, the hand function domain of the Stroke Impact Scale, which documents difficulty of hand motor usage, and the amount of use portion of the Motor Activity Log, which records amount of arm motor usage. The 43 participants had mild disability (median modified Rankin Scale=2), moderate motor deficits (Fugl-Meyer motor scale=46 ± 22), and mild cognitive/language deficits. The 2 patient-reported outcome measures, Stroke Impact Scale and Motor Activity Log, were sensitive to the presence of arm motor deficits. Of 21 patients classified as having minimal or no impairment or disability by the National Institutes of Health Stroke Scale or modified Rankin Scale (score of 0-1), 15 (71%) reported difficulty with hand movements by the Stroke Impact Scale score or reduced arm use by the Motor Activity Log score. Furthermore, of 14 patients with a normal examination, 10 (71%) reported difficulty with hand movements or reduction in arm use. Patient-reported measures were a unique source of insight into clinical status in the current population. Motor deficits were revealed in a majority of patients classified by standard scales as having minimal or no disability, and in a majority of patients classified as having no deficits.

  14. Neurone-specific enolase and N-acetyl-aspartate as potential peripheral markers of ischaemic stroke

    NARCIS (Netherlands)

    Stevens, H; Jakobs, C; de Jager, AEJ; Cunningham, RT; Korf, J

    Background After stroke, brain-specific proteins (including neurone-specific enolase) leak into the blood. The question addressed in the present study was whether N-acetyl-aspartate (amino acid derivative localized in cerebral neurones) could also serve as a peripheral marker of ischaemic damage.

  15. Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons

    Science.gov (United States)

    Magrané, Jordi; Sahawneh, Mary Anne; Przedborski, Serge; Estévez, Álvaro G.; Manfredi, Giovanni

    2012-01-01

    Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Taken together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS. PMID:22219285

  16. Evaluating motor recovery early after stroke: comparison of the Fugl-Meyer Assessment and the Motor Assessment Scale.

    Science.gov (United States)

    Malouin, F; Pichard, L; Bonneau, C; Durand, A; Corriveau, D

    1994-11-01

    This study compared the measurements of the Motor Assessment Scale (MAS) to that of the Fugl-Meyer Assessment (FMA), a reliable and valid test for motor function in stroke patients. Thirty-two patients (20 men, 12 women) with a mean age of 60 years, and a mean time since stroke of 64.5 days, were tested with the FMA and MAS on two consecutive days. The Spearman correlation coefficient for total FMA and total MAS scores was 0.96. For selected items, significant (p scale can better discriminate the level of motor recovery than the MAS in the early stage of recovery or in the more disabled subjects.

  17. Ipsilateral motor pathways after stroke: implications for noninvasive brain stimulation

    Directory of Open Access Journals (Sweden)

    Lynley V Bradnam

    2013-05-01

    Full Text Available In humans the two cerebral hemispheres have essential roles in controlling the upper limb. The purpose of this article is to draw attention to the potential importance of ipsilateral descending pathways for functional recovery after stroke, and the use of noninvasive brain stimulation (NBS protocols of the contralesional primary motor cortex (M1. Conventionally NBS is used to suppress contralesional M1, and to attenuate transcallosal inhibition onto the ipsilesional M1. There has been little consideration of the fact that contralesional M1 suppression may also reduce excitability of ipsilateral descending pathways that may be important for paretic upper limb control for some patients. One such ipsilateral pathway is the cortico-reticulo-propriospinal pathway (CRPP. In this review we outline a neurophysiological model to explain how contralesional M1 may gain control of the paretic arm via the CRPP. We conclude that the relative importance of the CRPP for motor control in individual patients must be considered before using NBS to suppress contralesional M1. Neurophysiological, neuroimaging and clinical assessments can assist this decision making and facilitate the translation of NBS into the clinical setting.

  18. Axial diffusivity changes in the motor pathway above stroke foci and functional recovery after subcortical infarction.

    Science.gov (United States)

    Liu, Gang; Peng, Kangqiang; Dang, Chao; Tan, Shuangquan; Chen, Hongbing; Xie, Chuanmiao; Xing, Shihui; Zeng, Jinsheng

    2018-01-01

    Secondary degeneration of the fiber tract of the motor pathway below infarct foci and functional recovery after stroke have been well demonstrated, but the role of the fiber tract above stroke foci remains unclear. This study aimed to investigate diffusion changes in motor fibers above the lesion and identify predictors of motor improvement within 12 weeks after subcortical infarction. Diffusion tensor imaging and the Fugl-Meyer (FM) scale were conducted 1, 4, and 12 weeks (W) after a subcortical infarct. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Region of interest analysis was used to assess diffusion changes in the motor pathway above and below a stroke lesion. Multivariable linear regression was employed to identify predictors of motor improvement within 12 weeks after stroke. Axial diffusivity (AD) in the underlying white matter of the ipsilesional primary motor area (PMA) and cerebral peduncle (CP) in both proportional and poor recovery groups was lower at W1 compared to the controls and values in the contralesional PMA and CP (all P < 0.05). Subsequently, AD in the ipsilesional CP became relatively stable, while AD in the ipsilesional PMA significantly increased from W4 to W12 after stroke (P < 0.05). In all of the patients, changes in the FM scores were greater in those with higher changes in AD of the ipsilesional PMA. Only initial impairment or lesion volume was predictive of motor improvement within 12 weeks after stroke in patients with proportional or poor recovery. Increases of AD in the motor pathway above stroke foci may be associated with motor recovery after subcortical infarction. Early measurement of diffusion metrics in the ipsilesional non-ischemic motor pathway has limited value in predicting future motor improvement patterns (proportional or poor recovery).

  19. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke.

    Science.gov (United States)

    Clarkson, Andrew N; Overman, Justine J; Zhong, Sheng; Mueller, Rudolf; Lynch, Gary; Carmichael, S Thomas

    2011-03-09

    Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.

  20. Novel peripheral motor neurons in the posterior tentacles of the snail responsible for local tentacle movements.

    Science.gov (United States)

    Hernádi, László; Kiss, Tibor; Krajcs, Nóra; Teyke, Thomas

    2014-09-01

    Three flexor muscles of the posterior tentacles of the snail Helix pomatia have recently been described. Here, we identify their local motor neurons by following the retrograde transport of neurobiotin injected into these muscles. The mostly unipolar motor neurons (15-35 µm) are confined to the tentacle digits and send motor axons to the M2 and M3 muscles. Electron microscopy revealed small dark neurons (5-7 µm diameter) and light neurons with 12-18 (T1 type) and 18-30 µm diameters (T2 type) in the digits. The diameters of the neurobiotin-labeled neurons corresponded to the T1 type light neurons. The neuronal processes of T1 type motor neurons arborize extensively in the neuropil area of the digits and receive synaptic inputs from local neuronal elements involved in peripheral olfactory information processing. These findings support the existence of a peripheral stimulus-response pathway, consisting of olfactory stimulus-local motor neuron-motor response components, to generate local lateral movements of the tentacle tip ("quiver"). In addition, physiological results showed that each flexor muscle receives distinct central motor commands via different peritentacular nerves and common central motor commands via tentacle digits, respectively. The distal axonal segments of the common pathway can receive inputs from local interneurons in the digits modulating the motor axon activity peripherally without soma excitation. These elements constitute a local microcircuit consisting of olfactory stimulus-distal segments of central motor axons-motor response components, to induce patterned contraction movements of the tentacle. The two local microcircuits described above provide a comprehensive neuroanatomical basis of tentacle movements without the involvement of the CNS.

  1. Lower motor neuron involvement examined by quantitative electromyography in amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Krarup, Christian

    2011-01-01

    Objective The diagnosis of amyotrophic lateral sclerosis (ALS) includes demonstration of lower motor neuron (LMN) and upper motor neuron (UMN) involvement of bulbar and spinal muscles. Electromyography (EMG) is essential to confirm LMN affection in weak muscles, and to demonstrate changes...

  2. The alluring but misleading analogy between mirror neurons and the motor theory of speech.

    Science.gov (United States)

    Holt, Lori L; Lotto, Andrew J

    2014-04-01

    Speech is commonly claimed to relate to mirror neurons because of the alluring surface analogy of mirror neurons to the Motor Theory of speech perception, which posits that perception and production draw upon common motor-articulatory representations. We argue that the analogy fails and highlight examples of systems-level developmental approaches that have been more fruitful in revealing perception-production associations.

  3. Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy

    NARCIS (Netherlands)

    Raaphorst, J.; de Visser, M.; van Tol, M.-J.; Linssen, W.H.J.P.; van der Kooi, A.J.; de Haan, R.J.; van den Berg, L.H.; Schmand, B.

    2011-01-01

    Aim In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to

  4. PELATIHAN MIRROR NEURON SYSTEM SAMA DENGAN PELATIHAN CONSTRAINT INDUCED MOVEMENT THERAPY DALAM MENINGKATKAN KEMAMPUAN FUNGSIONAL ANGGOTA GERAK ATAS PASIEN STROKE

    Directory of Open Access Journals (Sweden)

    Abdul chalik meidian

    2014-03-01

    Full Text Available Stroke is an interruption of blood vasculature system in the brain that causes suddenly neurological dysfunction, resulted in clinically brain tissue damage in a relatively long time period, decreased physical mobility and functional ability impaired of upper limb. The purpose of this study is to know an increasing in upper limb functional ability among stroke patients after mirror neuron system exercise and constraint induced movement therapy exercise and to know the comparison of both exercise. This study uses an experimental research with pre-test and post-test control group design. Number of samples of the first group is 13 patients given mirror neuron system exercise for 30-60 minutes , while the second group 13 patients were given constraint induced movement therapy exercise for 30-60 minutes. The research was conducted in 2 month period time. Each patient is taught a variety of upper limb functional ability in accordance with the operational concept guidance and patients were asked to repeat the exercise independently at home as directed. Measuring test of upper limb functional ability is using the wolf motor function test instruments. The result is an increase the upper limb functional ability of 21.7% in the mirror neuron system exercise group and proved a significant difference (p<0.05 and an increase in the upper limb functional ability of 17.1% in the constraint induced movement therapy exercise group and proved a significant difference (p<0.05 while the difference of increasing of upper limb functional ability of the two groups showed no significant difference (p>0,05. It was concluded that the mirror neuron system exercise is similar with constraint induced movement therapy exercise in increasing the upper limb functional ability among stroke patients.

  5. Correlative study between neuron-specific enolase and blood sugar level in ischemic stroke patients

    Directory of Open Access Journals (Sweden)

    Aparna Pandey

    2011-01-01

    Full Text Available Background: A study to investigate the level of the neurobiochemical marker, Neuron-Specific Enolase (NSE, at the time of admission and its correlation with the blood sugar level in ischemic stroke patients. Patients and Methods: We investigated 90 patients with complete stroke who were admitted to the Stroke Unit of the Department of Neurology at Sri Aurobindo Institute of Medical Sciences. NSE was measured with commercially available quantitative ′sandwich′ enzyme-linked immunosorbent assay kits obtained from R and D Systems. Hyperglycemia was defined as blood glucose concentration ≥ 7 mmol / L, and measured using the glucose oxidase method immediately. Results: Significantly increased NSE and lipid profile levels were found in ischemic stroke patients as compared to the control. Hyperglycemic ischemic stroke patients had increased levels of NSE, lipid profile, and National Institute of Health stroke scale scores (NIHSS score compared to normoglycemic ischemic stroke patients. In addition the serum NSE level of hyperglycemic stroke patients was also positively correlated with the blood sugar level (r = 0.734 P < 0.001. Conclusions: Hyperglycemia predicts an increased risk of poor outcome after ischemic stroke and it is reflected by a significantly increased level of Neuron-Specific Enolase.

  6. Stress exacerbates neuron loss and microglia proliferation in a rat model of excitotoxic lower motor neuron injury.

    Science.gov (United States)

    Puga, Denise A; Tovar, C Amy; Guan, Zhen; Gensel, John C; Lyman, Matthew S; McTigue, Dana M; Popovich, Phillip G

    2015-10-01

    All individuals experience stress and hormones (e.g., glucocorticoids/GCs) released during stressful events can affect the structure and function of neurons. These effects of stress are best characterized for brain neurons; however, the mechanisms controlling the expression and binding affinity of glucocorticoid receptors in the spinal cord are different than those in the brain. Accordingly, whether stress exerts unique effects on spinal cord neurons, especially in the context of pathology, is unknown. Using a controlled model of focal excitotoxic lower motor neuron injury in rats, we examined the effects of acute or chronic variable stress on spinal cord motor neuron survival and glial activation. New data indicate that stress exacerbates excitotoxic spinal cord motor neuron loss and associated activation of microglia. In contrast, hypertrophy and hyperplasia of astrocytes and NG2+ glia were unaffected or were modestly suppressed by stress. Although excitotoxic lesions cause significant motor neuron loss and stress exacerbates this pathology, overt functional impairment did not develop in the relevant forelimb up to one week post-lesion. These data indicate that stress is a disease-modifying factor capable of altering neuron and glial responses to pathological challenges in the spinal cord. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

    Science.gov (United States)

    Boyd, Penelope J; Tu, Wen-Yo; Shorrock, Hannah K; Groen, Ewout J N; Carter, Roderick N; Powis, Rachael A; Thomson, Sophie R; Thomson, Derek; Graham, Laura C; Motyl, Anna A L; Wishart, Thomas M; Highley, J Robin; Morton, Nicholas M; Becker, Thomas; Becker, Catherina G; Heath, Paul R; Gillingwater, Thomas H

    2017-04-01

    Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

  8. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-06-01

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  9. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Penelope J Boyd

    2017-04-01

    Full Text Available Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA, resulting from low levels of ubiquitously-expressed survival motor neuron (SMN protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant, gastrocnemius (intermediate vulnerability, and tibialis anterior (vulnerable muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1, was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1, rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

  10. A case of cervical radiation radiculopathy resembling motor neuron disease

    International Nuclear Information System (INIS)

    Mitsunaga, Yoshihiro; Yoshimura, Takeo; Hara, Hideo; Yamada, Takeshi; Kira, Jun-ichi; Kobayashi, Takuro

    1998-01-01

    A 67-year-old man developed slowly progressive muscular weakness in the bilateral upper extremities (C5-7 regions) without signs of sensory deficit following the cervical radiation therapy (70.5 Gy) for right laryngeal cancer 4 years before. These clinical signs resembled those of lower motor neuron disease. MRI with gadolinium-DTPA, however, showed enhancement in the bilateral C5 and C6 anterior roots, suggesting the cervical radiculopathy due to radiotherapy. It is known that radiation to the spinal cord can lead to ''selective anterior horn cell injury''. This is the first case report of the cervical radiation radiculopathy, which, if without MRI, might be classified into selective anterior horn cell injury. Suggestion is made for the hypothesis that the spinal motoneuron loss in radiation myelopathy would be caused by retrograde degeneration due to anterior root damages. (author)

  11. A case of cervical radiation radiculopathy resembling motor neuron disease

    Energy Technology Data Exchange (ETDEWEB)

    Mitsunaga, Yoshihiro; Yoshimura, Takeo; Hara, Hideo; Yamada, Takeshi; Kira, Jun-ichi; Kobayashi, Takuro [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1998-05-01

    A 67-year-old man developed slowly progressive muscular weakness in the bilateral upper extremities (C5-7 regions) without signs of sensory deficit following the cervical radiation therapy (70.5 Gy) for right laryngeal cancer 4 years before. These clinical signs resembled those of lower motor neuron disease. MRI with gadolinium-DTPA, however, showed enhancement in the bilateral C5 and C6 anterior roots, suggesting the cervical radiculopathy due to radiotherapy. It is known that radiation to the spinal cord can lead to ``selective anterior horn cell injury``. This is the first case report of the cervical radiation radiculopathy, which, if without MRI, might be classified into selective anterior horn cell injury. Suggestion is made for the hypothesis that the spinal motoneuron loss in radiation myelopathy would be caused by retrograde degeneration due to anterior root damages. (author)

  12. Intracerebroventricular Delivery in Mice for Motor Neuron Diseases.

    Science.gov (United States)

    Nizzardo, M; Rizzuti, M

    2017-01-01

    The use of antisense oligonucleotides to target specific mRNA sequences represents a promising therapeutic strategy for neurological disorders. Recent advances in antisense technology enclose the development of phosphorodiamidate morpholino oligomers (MO), which is one of the best candidates for molecular therapies due to MO's excellent pharmacological profile.Nevertheless, the route of administration of antisense compounds represents a critical issue in the neurological field. Particularly, as regards motor neuron diseases, intracerebroventricular (ICV) injection is undoubtedly the most efficient procedure to directly deliver therapeutic molecules in the central nervous system (CNS). Indeed, we recently demonstrated the outstanding efficacy of the MO antisense approach by its direct administration to CNS of the transgenic mouse models of Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS).Here, we describe methods to perform the ICV delivery of MO in neonatal SMA mice and in adult ALS mice.

  13. Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons.

    Science.gov (United States)

    Fallini, Claudia; Rouanet, Jeremy P; Donlin-Asp, Paul G; Guo, Peng; Zhang, Honglai; Singer, Robert H; Rossoll, Wilfried; Bassell, Gary J

    2014-03-01

    Spinal muscular atrophy (SMA) is a lethal neurodegenerative disease specifically affecting spinal motor neurons. SMA is caused by the homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene. The SMN protein plays an essential role in the assembly of spliceosomal ribonucleoproteins. However, it is still unclear how low levels of the ubiquitously expressed SMN protein lead to the selective degeneration of motor neurons. An additional role for SMN in the regulation of the axonal transport of mRNA-binding proteins (mRBPs) and their target mRNAs has been proposed. Indeed, several mRBPs have been shown to interact with SMN, and the axonal levels of few mRNAs, such as the β-actin mRNA, are reduced in SMA motor neurons. In this study we have identified the β-actin mRNA-binding protein IMP1/ZBP1 as a novel SMN-interacting protein. Using a combination of biochemical assays and quantitative imaging techniques in primary motor neurons, we show that IMP1 associates with SMN in individual granules that are actively transported in motor neuron axons. Furthermore, we demonstrate that IMP1 axonal localization depends on SMN levels, and that SMN deficiency in SMA motor neurons leads to a dramatic reduction of IMP1 protein levels. In contrast, no difference in IMP1 protein levels was detected in whole brain lysates from SMA mice, further suggesting neuron specific roles of SMN in IMP1 expression and localization. Taken together, our data support a role for SMN in the regulation of mRNA localization and axonal transport through its interaction with mRBPs such as IMP1. Copyright © 2013 Wiley Periodicals, Inc.

  14. Structurofunctional resting-state networks correlate with motor function in chronic stroke

    Directory of Open Access Journals (Sweden)

    Benjamin T. Kalinosky

    2017-01-01

    Conclusion: The results demonstrate that changes after a stroke in both intrinsic and network-based structurofunctional correlations at rest are correlated with motor function, underscoring the importance of residual structural connectivity in cortical networks.

  15. Non-viral gene therapy that targets motor neurons in vivo

    Science.gov (United States)

    Rogers, Mary-Louise; Smith, Kevin S.; Matusica, Dusan; Fenech, Matthew; Hoffman, Lee; Rush, Robert A.; Voelcker, Nicolas H.

    2014-01-01

    A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS). We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by “immunogene” nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12) as DNA carrier was conjugated to an antibody (MLR2) to the neurotrophin receptor p75 (p75NTR). We used a plasmid (pVIVO2) designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP). MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice, GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0% of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo. PMID:25352776

  16. Non-viral gene therapy that targets motor neurons in vivo

    Directory of Open Access Journals (Sweden)

    Mary-Louise eRogers

    2014-10-01

    Full Text Available A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS. We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by ‘immunogene’ nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12 as DNA carrier was conjugated to an antibody (MLR2 to the neurotrophin receptor p75 (p75NTR. We used a plasmid (pVIVO2 designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP. MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0 % of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo.

  17. Spinal muscular atrophy: Selective motor neuron loss and global defect in the assembly of ribonucleoproteins.

    Science.gov (United States)

    Beattie, Christine E; Kolb, Stephen J

    2018-02-17

    Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair. Thus, SMA is an exemplar, selective motor neuron disorder that is caused by defects in fundamental RNA processing events. A detailed molecular understanding of how motor neurons fail, and why other neurons do not, in SMA will yield important principals about motor neuron maintenance and neuronal specificity in neurodegenerative diseases. Copyright © 2018. Published by Elsevier B.V.

  18. Neuronal mechanisms of motor learning are age dependent.

    Science.gov (United States)

    Berghuis, Kelly M M; De Rond, Veerle; Zijdewind, Inge; Koch, Giacomo; Veldman, Menno P; Hortobágyi, Tibor

    2016-10-01

    There is controversy whether age-related neuroanatomical and neurophysiological changes in the central nervous system affect healthy old adults' abilities to acquire and retain motor skills. We examined the effects of age on motor skill acquisition and retention and potential underlying mechanisms by measuring corticospinal and intracortical excitability, using transcranial magnetic stimulation. Healthy young (n = 24, 22 years) and old (n = 22, 71 years) adults practiced a wrist flexion-extention visuomotor task or only watched the templates as an attentional control for 20 minutes. Old compared with young adults performed less well at baseline. Although the absolute magnitude of skill acquisition and retention was similar in the 2 age groups (age × intervention × time, p = 0.425), a comparison of baseline-similar age sub-groups revealed impaired skill acquisition but not retention in old versus young. Furthermore, the neuronal mechanisms differed as revealed by an opposite direction of associations in the age-groups between relative skill acquisition and intracortical facilitation during the task, and opposite changes during skill retention in corticospinal excitability at rest and during the task and intracortical inhibition during the task. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The spasticity in the motor and functional disability in adults with post-stroke hemiparetic

    OpenAIRE

    Cacho, Roberta de Oliveira; Cacho, Enio Walker Azevedo; Loureiro, Anderson Barbosa; Cirne, Gabriele Natane de Medeiros; Pereira, Silvana Alves; Freitas, Rodrigo Pegado de Abreu; Lima, Núbia Maria Freire Vieira; Borges, Guilherme

    2017-01-01

    Abstract Introduction: Spasticity acts as a limiting factor in motor and functional recovery after Stroke, impairing the performance of daily living activities. Objective: To analyze the influence of spasticity on main muscle groups and to associate it with motor impairment and functional level of chronic hemiparetic patients after stroke. Methods: Twenty-seven chronic hemiparetic patients of both sexes were selected at the Physical Therapy and Occupational Therapy Service of the Unicamp...

  20. functional motor recovery in stroke survivors-determinants in a sub

    African Journals Online (AJOL)

    2014-04-01

    Apr 1, 2014 ... giving a drop-out rate of one in four (1:4) and all enrollees were only admitted and discharged patients in the stroke unit. Stroke type was categorised as cerebral infarct and intracerebral haemorrhage. Operationally functional motor recovery was defined by at least a two point reduction in modified.

  1. Accelerated high-yield generation of limb-innervating motor neurons from human stem cells

    Science.gov (United States)

    Amoroso, Mackenzie W.; Croft, Gist F.; Williams, Damian J.; O’Keeffe, Sean; Carrasco, Monica A.; Davis, Anne R.; Roybon, Laurent; Oakley, Derek H.; Maniatis, Tom; Henderson, Christopher E.; Wichterle, Hynek

    2013-01-01

    Human pluripotent stem cells are a promising source of differentiated cells for developmental studies, cell transplantation, disease modeling, and drug testing. However, their widespread use even for intensely studied cell types like spinal motor neurons is hindered by the long duration and low yields of existing protocols for in vitro differentiation and by the molecular heterogeneity of the populations generated. We report a combination of small molecules that within 3 weeks induce motor neurons at up to 50% abundance and with defined subtype identities of relevance to neurodegenerative disease. Despite their accelerated differentiation, motor neurons expressed combinations of HB9, ISL1 and column-specific markers that mirror those observed in vivo in human fetal spinal cord. They also exhibited spontaneous and induced activity, and projected axons towards muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1+/LHX3−). Access to high-yield cultures of human limb-innervating motor neuron subtypes will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays. PMID:23303937

  2. Motor imagery cognitive network after left ischemic stroke: study of the patients during mental rotation task.

    Directory of Open Access Journals (Sweden)

    Jing Yan

    Full Text Available Although motor imagery could improve motor rehabilitation, the detailed neural mechanisms of motor imagery cognitive process of stroke patients, particularly from functional network perspective, remain unclear. This study investigated functional brain network properties in each cognitive sub-stage of motor imagery of stroke patients with ischemic lesion in left hemisphere to reveal the impact of stroke on the cognition of motor imagery. Both stroke patients and control subjects participated in mental rotation task, which includes three cognitive sub-stages: visual stimulus perception, mental rotation and response cognitive process. Event-related electroencephalograph was recorded and interdependence between two different cortical areas was assessed by phase synchronization. Both global and nodal properties of functional networks in three sub-stages were statistically analyzed. Phase synchronization of stroke patients significantly reduced in mental rotation sub-stage. Longer characteristic path length and smaller global clustering coefficient of functional network were observed in patients in mental rotation sub-stage which implied the impaired segregation and integration. Larger nodal clustering coefficient and betweenness in contralesional occipitoparietal and frontal area respectively were observed in patients in all sub-stages. In addition, patients also showed smaller betweenness in ipsilesional central-parietal area in response sub-stage. The compensatory effects on local connectedness and centrality indicated the neuroplasticity in contralesional hemisphere. The functional brain networks of stroke patients demonstrated significant alterations and compensatory effects during motor imagery.

  3. Rapid, efficient, and simple motor neuron differentiation from human pluripotent stem cells.

    Science.gov (United States)

    Shimojo, Daisuke; Onodera, Kazunari; Doi-Torii, Yukiko; Ishihara, Yasuharu; Hattori, Chinatsu; Miwa, Yukino; Tanaka, Satoshi; Okada, Rina; Ohyama, Manabu; Shoji, Masanobu; Nakanishi, Atsushi; Doyu, Manabu; Okano, Hideyuki; Okada, Yohei

    2015-12-01

    Human pluripotent stem cells (hPSCs) are being applied in regenerative medicine and for the in vitro modeling of human intractable disorders. In particular, neural cells derived from disease-specific human induced pluripotent stem cells (hiPSCs) established from patients with neurological disorders have been used as in vitro disease models to recapitulate in vivo pathogenesis because neural cells cannot be usually obtained from patients themselves. In this study, we established a rapid, efficient, and simple method for efficiently deriving motor neurons from hPSCs that is useful for pathophysiological analysis and the development of drugs to treat motor neuron diseases. Treatment with GSK3β inhibitors during the initial phase of differentiation in combination with dual SMAD inhibition was sufficient to induce PAX6 (+) and SOX1 (+) neural progenitors within 1 week, and subsequent treatment with retinoic acid (RA) and purmorphamine, which activates sonic hedgehog (SHH) signaling, resulted in the highly efficient induction of HB9(+) and ISL-1(+) motor neurons within 2 weeks. After 4 weeks of monolayer differentiation in motor neuron maturation medium, hPSC-derived motor neurons were shown to mature, displaying larger somas and clearer staining for the mature motor neuron marker choline acetyltransferase (ChAT). Moreover, hPSC-derived motor neurons were able to form neuromuscular junctions with human myotubes in vitro and induced acetylcholine receptor (AChR) clustering, as detected by Alexa 555-conjugated α-Bungarotoxin (α-BTX), suggesting that these hPSC-derived motor neurons formed functional contacts with skeletal muscles. This differentiation system is simple and is reproducible in several hiPSC clones, thereby minimizing clonal variation among hPSC clones. We also established a system for visualizing motor neurons with a lentiviral reporter for HB9 (HB9 (e438) ::Venus). The specificity of this reporter was confirmed through immunocytochemistry and

  4. Time configuration of combined neuromodulation and motor training after stroke: A proof-of-concept study.

    Science.gov (United States)

    Powell, Elizabeth S; Carrico, Cheryl; Westgate, Philip M; Chelette, Kenneth C; Nichols, Laurie; Reddy, Lakshmi; Salyers, Emily; Ward, Andrea; Sawaki, Lumy

    2016-07-15

    Intensive motor training is a therapeutic intervention that supports recovery of movement function after stroke by capitalizing on the brain's capacity for neuroplastic change. Peripheral nerve stimulation and transcranial direct current stimulation are neuromodulation techniques that can upregulate neuroplasticity and, in turn, enhance outcomes of motor training after stroke. Few studies have investigated possible adjuvant effects between peripheral nerve stimulation, transcranial direct current stimulation, and intensive motor training. This proof-of-concept study investigated whether timing variations in neuromodulation paired with robot-assisted motor training effect differential outcomes for subjects with chronic, moderate-to-severe upper extremity impairment after stroke. Ten subjects in the chronic phase (>12 months after stroke) of recovery completed the study. Subjects received 10 daily sessions of transcranial direct current stimulation either at the start (n = 4) or at the end (n = 6) of peripheral nerve stimulation preceding intensive motor training. Pre-post changes in motor function (Fugl-Meyer Assessment; Stroke Impact Scale) and neuroplasticity (transcranial magnetic stimulation) were assessed by condition. Significant improvement in Stroke Impact Scale (p = 0.02) and no change in Fugl-Meyer Assessment were associated with the start condition. No changes in Stroke Impact Scale and Fugl-Meyer Assessment were associated with the end condition. Only 1 subject in the start group had measurable neuroplastic responses and demonstrated an increase in ipsilesional cortical map volume. Only 1 subject in the end group had measurable neuroplastic responses and demonstrated a decrease in ipsilesional cortical map volume. Opposite shifts in ipsilesional cortical centers of gravity occurred relative to condition. In cases of moderate-to-severe impairment after stroke, transcranial direct current stimulation at the start, rather than the end, of

  5. Neural coupling between contralesional motor and frontoparietal networks correlates with motor ability in individuals with chronic stroke.

    Science.gov (United States)

    Lam, Timothy K; Dawson, Deirdre R; Honjo, Kie; Ross, Bernhard; Binns, Malcolm A; Stuss, Donald T; Black, Sandra E; Chen, J Jean; Levine, Brian T; Fujioka, Takako; Chen, Joyce L

    2018-01-15

    Movement is traditionally viewed as a process that involves motor brain regions. However, movement also implicates non-motor regions such as prefrontal and parietal cortex, regions whose integrity may thus be important for motor recovery after stroke. Importantly, focal brain damage can affect neural functioning within and between distinct brain networks implicated in the damage. The aim of this study is to investigate how resting state connectivity (rs-connectivity) within and between motor and frontoparietal networks are affected post-stroke in correlation with motor outcome. Twenty-seven participants with chronic stroke with unilateral upper limb deficits underwent motor assessments and magnetic resonance imaging. Participants completed the Chedoke-McMaster Stroke Assessment as a measure of arm (CMSA-Arm) and hand (CMSA-Hand) impairment and the Action Research Arm Test (ARAT) as a measure of motor function. We used a seed-based rs-connectivity approach defining the motor (seed=contralesional primary motor cortex (M1)) and frontoparietal (seed=contralesional dorsolateral prefrontal cortex (DLPFC)) networks. We analyzed the rs-connectivity within each network (intra-network connectivity) and between both networks (inter-network connectivity), and performed correlations between: a) intra-network connectivity and motor assessment scores; b) inter-network connectivity and motor assessment scores. We found: a) Participants with high rs-connectivity within the motor network (between M1 and supplementary motor area) have higher CMSA-Hand stage (z=3.62, p=0.003) and higher ARAT score (z=3.41, p=0.02). Rs-connectivity within the motor network was not significantly correlated with CMSA-Arm stage (z=1.83, p>0.05); b) Participants with high rs-connectivity within the frontoparietal network (between DLPFC and mid-ventrolateral prefrontal cortex) have higher CMSA-Hand stage (z=3.64, p=0.01). Rs-connectivity within the frontoparietal network was not significantly correlated

  6. The critical role of membralin in postnatal motor neuron survival and disease.

    Science.gov (United States)

    Yang, Bo; Qu, Mingliang; Wang, Rengang; Chatterton, Jon E; Liu, Xiao-Bo; Zhu, Bing; Narisawa, Sonoko; Millan, Jose Luis; Nakanishi, Nobuki; Swoboda, Kathryn; Lipton, Stuart A; Zhang, Dongxian

    2015-05-15

    Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

  7. [The rehabilitation treatment of patients with motor and cognitive disorders after stroke].

    Science.gov (United States)

    Sakharov, V Iu; Isanova, V A

    2014-01-01

    Objective. To study the possibility of using the rehabilitative pneumatic suit "Atlant" in stroke outpatients. Material and methods. We studied 11 stroke patients who wore the pneumatic suit in the early rehabilitation period. A comparison group included 13 patients. The high effectiveness of complex treatment with using the suit "Atlant" was shown. The motor activity was improved in 71.4% of patients, the recovery of speech was found in 33.3% patients. Conclusion. Continuity of rehabilitation in outpatients with stroke promotes the recovery of functional activity, motor, cognitive and speech functions and positively impacts on the emotional state of the patient.

  8. Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex.

    Science.gov (United States)

    Jara, J H; Stanford, M J; Zhu, Y; Tu, M; Hauswirth, W W; Bohn, M C; DeVries, S H; Özdinler, P H

    2016-03-01

    Direct gene delivery to the neurons of interest, without affecting other neuron populations in the cerebral cortex, represent a challenge owing to the heterogeneity and cellular complexity of the brain. Genetic modulation of corticospinal motor neurons (CSMN) is required for developing effective and long-term treatment strategies for motor neuron diseases, in which voluntary movement is impaired. Adeno-associated viruses (AAV) have been widely used for neuronal transduction studies owing to long-term and stable gene expression as well as low immunoreactivity in humans. Here we report that AAV2-2 transduces CSMN with high efficiency upon direct cortex injection and that transduction efficiencies are similar during presymptomatic and symptomatic stages in hSOD1(G93A) transgenic amyotrophic lateral sclerosis (ALS) mice. Our findings reveal that choice of promoter improves selectivity as AAV2-2 chicken β-actin promoter injection results in about 70% CSMN transduction, the highest percentage reported to date. CSMN transduction in both wild-type and transgenic ALS mice allows detailed analysis of single axon fibers within the corticospinal tract in both cervical and lumbar spinal cord and reveals circuitry defects, which mainly occur between CSMN and spinal motor neurons in hSOD1(G93A) transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases.

  9. Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy

    Directory of Open Access Journals (Sweden)

    Luis B Tovar-y-Romo

    2014-02-01

    Full Text Available Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF, glial-derived neurotrophic factor (GDNF, ciliary neurotrophic factor (CNTF and insulin-like growth factor 1 (IGF-1. Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this review we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.

  10. Optogenetically enhanced axon regeneration: motor versus sensory neuron-specific stimulation.

    Science.gov (United States)

    Ward, Patricia J; Clanton, Scott L; English, Arthur W

    2018-02-01

    Brief neuronal activation in injured peripheral nerves is both necessary and sufficient to enhance motor axon regeneration, and this effect is specific to the activated motoneurons. It is less clear whether sensory neurons respond in a similar manner to neuronal activation following peripheral axotomy. Further, it is unknown to what extent enhancement of axon regeneration with increased neuronal activity relies on a reflexive interaction within the spinal circuitry. We used mouse genetics and optical tools to evaluate the precision and selectivity of system-specific neuronal activation to enhance axon regeneration in a mixed nerve. We evaluated sensory and motor axon regeneration in two different mouse models expressing the light-sensitive cation channel, channelrhodopsin (ChR2). We selectively activated either sensory or motor axons using light stimulation combined with transection and repair of the sciatic nerve. Regardless of genotype, the number of ChR2-positive neurons whose axons had regenerated successfully was greater following system-specific optical treatment, with no effect on the number of ChR2-negative neurons (whether motor or sensory neurons). We conclude that acute system-specific neuronal activation is sufficient to enhance both motor and sensory axon regeneration. This regeneration-enhancing effect is likely cell autonomous. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  11. Motor Imagery-Based Rehabilitation: Potential Neural Correlates and Clinical Application for Functional Recovery of Motor Deficits after Stroke.

    Science.gov (United States)

    Tong, Yanna; Pendy, John T; Li, William A; Du, Huishan; Zhang, Tong; Geng, Xiaokun; Ding, Yuchuan

    2017-05-01

    Motor imagery (MI), defined as the mental implementation of an action in the absence of movement or muscle activation, is a rehabilitation technique that offers a means to replace or restore lost motor function in stroke patients when used in conjunction with conventional physiotherapy procedures. This article briefly reviews the concepts and neural correlates of MI in order to promote improved understanding, as well as to enhance the clinical utility of MI-based rehabilitation regimens. We specifically highlight the role of the cerebellum and basal ganglia, premotor, supplementary motor, and prefrontal areas, primary motor cortex, and parietal cortex. Additionally, we examine the recent literature related to MI and its potential as a therapeutic technique in both upper and lower limb stroke rehabilitation.

  12. Motor neuron derivation from human embryonic and induced pluripotent stem cells: experimental approaches and clinical perspectives.

    Science.gov (United States)

    Faravelli, Irene; Bucchia, Monica; Rinchetti, Paola; Nizzardo, Monica; Simone, Chiara; Frattini, Emanuele; Corti, Stefania

    2014-07-14

    Motor neurons are cells located in specific areas of the central nervous system, such as brain cortex (upper motor neurons), brain stem, and spinal cord (lower motor neurons), which maintain control over voluntary actions. Motor neurons are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs): these disorders share symptoms related to muscular atrophy and paralysis leading to death. No effective treatments are currently available. Stem cell-derived motor neurons represent a promising research tool in disease modeling, drug screening, and development of therapeutic approaches for MNDs and spinal cord injuries. Directed differentiation of human pluripotent stem cells - human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) - toward specific lineages is the first crucial step in order to extensively employ these cells in early human development investigation and potential clinical applications. Induced pluripotent stem cells (iPSCs) can be generated from patients' own somatic cells (for example, fibroblasts) by reprogramming them with specific factors. They can be considered embryonic stem cell-like cells, which express stem cell markers and have the ability to give rise to all three germ layers, bypassing the ethical concerns. Thus, hiPSCs constitute an appealing alternative source of motor neurons. These motor neurons might be a great research tool, creating a model for investigating the cellular and molecular interactions underlying early human brain development and pathologies during neurodegeneration. Patient-specific iPSCs may also provide the premises for autologous cell replacement therapies without related risks of immune rejection. Here, we review the most recent reported methods by which hESCs or iPSCs can be differentiated toward functional motor neurons with an overview on the potential clinical applications.

  13. Non-motor function of the midbrain dopaminergic neurons.

    Science.gov (United States)

    Da Cunha, Claudio; Wietzikoski, Evellyn Claudia; Bortolanza, Mariza; Dombrowski, Patricia Andréia; dos Santos, Lucélia Mendes; Boschen, Suelen Lúcio; Miyoshi, Edmar; Vital, Maria Aparecida Barbato Frazão; Boerngen-Lacerda, Roseli; Andreatini, Roberto

    2009-01-01

    The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.

  14. The effect of sleep on motor learning in the aging and stroke population - a systematic review.

    Science.gov (United States)

    Backhaus, W; Kempe, S; Hummel, F C

    2015-01-01

    There is extensive evidence for positive effects of sleep on motor learning in young individuals; however, the effects of sleep on motor learning in people with stroke and in healthy older individuals are not well understood. The aim of this systematic review was to quantify the association between sleep and procedural memory performance - a marker for motor learning - in healthy older people and people with stroke. After searches in PubMed, Medline and Embase fourteen studies, including 44 subjects after stroke and 339 healthy older participants were included. Overall, sleep was found to enhance motor performance in people after stroke in comparison to an equivalent time of wakefulness. In addition, although evidence is limited, sleep only enhanced motor performance in people after stroke and not in age-matched healthy older adults. In older adults the effect of a sleep intervention did - in general - not differ from equivalent periods of wakefulness. Tasks with whole hand or whole body movements could show significant changes. The results suggest a delayed retention effect after longer breaks including sleep, hinting towards a changed learning strategy as a result of aging. Current evidence for sleep dependent learning in people after stroke is promising, however sparse.

  15. Economic Studies in Motor Neurone Disease: A Systematic Methodological Review.

    Science.gov (United States)

    Moore, Alan; Young, Carolyn A; Hughes, Dyfrig A

    2017-04-01

    Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges. The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND. We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively. A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n = 9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location-specific characteristics. Few cost studies reported disease-stage-specific costs (n = 3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers. Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients.

  16. Correlations between motor and sensory functions in upper limb chronic hemiparetics after stroke

    Directory of Open Access Journals (Sweden)

    Thais Botossi Scalha

    2011-08-01

    Full Text Available OBJECTIVE: Describe the somatosensory function of the affected upper limb of hemiparetic stroke patients and investigate the correlations between measurements of motor and sensory functions in tasks with and without visual deprivation. METHOD: We applied the Fugl-Meyer Assessment (FMA, Nottingham Sensory Assessment (NSA, and several motor and sensory tests: Paper manipulation (PM, Motor Sequences (MS, Reaching and grasping (RG Tests Functional (TF, Tactile Discrimination (TD, Weight Discrimination (WD and Tactile Recognition of Objects (RO. RESULTS: We found moderate correlations between the FMA motor subscale and the tactile sensation score of the NSA. Additionally, the FMA sensitivity was correlated with the NSA total; and performance on the WD test items correlated with the NSA. CONCLUSION: There was a correlation between the sensory and motor functions of the upper limb in chronic hemiparetic stroke patients. Additionally, there was a greater reliance on visual information to compensate for lost sensory-motor skills.

  17. N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury.

    Science.gov (United States)

    Catapano, Joseph; Zhang, Jennifer; Scholl, David; Chiang, Cameron; Gordon, Tessa; Borschel, Gregory H

    2017-05-01

    Neuronal death may be an overlooked and unaddressed component of disability following neonatal nerve injuries, such as obstetric brachial plexus injury. N-acetylcysteine and acetyl-L-carnitine improve survival of neurons after adult nerve injury, but it is unknown whether they improve survival after neonatal injury, when neurons are most susceptible to retrograde neuronal death. The authors' objective was to examine whether N-acetylcysteine or acetyl-L-carnitine treatment improves survival of neonatal motor or sensory neurons in a rat model of neonatal nerve injury. Rat pups received either a sciatic nerve crush or transection injury at postnatal day 3 and were then randomized to receive either intraperitoneal vehicle (5% dextrose), N-acetylcysteine (750 mg/kg), or acetyl-L-carnitine (300 mg/kg) once or twice daily. Four weeks after injury, surviving neurons were retrograde-labeled with 4% Fluoro-Gold. The lumbar spinal cord and L4/L5 dorsal root ganglia were then harvested and sectioned to count surviving motor and sensory neurons. Transection and crush injuries resulted in significant motor and sensory neuron loss, with transection injury resulting in significantly less neuron survival. High-dose N-acetylcysteine (750 mg/kg twice daily) significantly increased motor neuron survival after neonatal sciatic nerve crush and transection injury. Neither N-acetylcysteine nor acetyl-L-carnitine treatment improved sensory neuron survival. Proximal neonatal nerve injuries, such as obstetric brachial plexus injury, produce significant retrograde neuronal death after injury. High-dose N-acetylcysteine significantly increases motor neuron survival, which may improve functional outcomes after obstetrical brachial plexus injury.

  18. Cognitive alterations in motor imagery process after left hemispheric ischemic stroke.

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    Jing Yan

    Full Text Available BACKGROUND: Motor imagery training is a promising rehabilitation strategy for stroke patients. However, few studies had focused on the neural mechanisms in time course of its cognitive process. This study investigated the cognitive alterations after left hemispheric ischemic stroke during motor imagery task. METHODOLOGY/PRINCIPAL FINDINGS: Eleven patients with ischemic stroke in left hemisphere and eleven age-matched control subjects participated in mental rotation task (MRT of hand pictures. Behavior performance, event-related potential (ERP and event-related (desynchronization (ERD/ERS in beta band were analyzed to investigate the cortical activation. We found that: (1 The response time increased with orientation angles in both groups, called "angle effect", however, stoke patients' responses were impaired with significantly longer response time and lower accuracy rate; (2 In early visual perceptual cognitive process, stroke patients showed hypo-activations in frontal and central brain areas in aspects of both P200 and ERD; (3 During mental rotation process, P300 amplitude in control subjects decreased while angle increased, called "amplitude modulation effect", which was not observed in stroke patients. Spatially, patients showed significant lateralization of P300 with activation only in contralesional (right parietal cortex while control subjects showed P300 in both parietal lobes. Stroke patients also showed an overall cortical hypo-activation of ERD during this sub-stage; (4 In the response sub-stage, control subjects showed higher ERD values with more activated cortical areas particularly in the right hemisphere while angle increased, named "angle effect", which was not observed in stroke patients. In addition, stroke patients showed significant lower ERD for affected hand (right response than that for unaffected hand. CONCLUSIONS/SIGNIFICANCE: Cortical activation was altered differently in each cognitive sub-stage of motor imagery after

  19. Birth of projection neurons in adult avian brain may be related to perceptual or motor learning

    International Nuclear Information System (INIS)

    Alvarez-Buylla, A.; Kirn, J.R.; Nottebohm, F.

    1990-01-01

    Projection neurons that form part of the motor pathway for song control continue to be produced and to replace older projection neurons in adult canaries and zebra finches. This is shown by combining [3H]thymidine, a cell birth marker, and fluorogold, a retrogradely transported tracer of neuronal connectivity. Species and seasonal comparisons suggest that this process is related to the acquisition of perceptual or motor memories. The ability of an adult brain to produce and replace projection neurons should influence our thinking on brain repair

  20. Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons.

    Science.gov (United States)

    Fallini, Claudia; Donlin-Asp, Paul G; Rouanet, Jeremy P; Bassell, Gary J; Rossoll, Wilfried

    2016-03-30

    Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily affecting spinal motor neurons. It is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays an essential role in the biogenesis of spliceosomal small nuclear ribonucleoproteins in all tissues. The etiology of the specific defects in the motor circuitry in SMA is still unclear, but SMN has also been implicated in mediating the axonal localization of mRNA-protein complexes, which may contribute to the axonal degeneration observed in SMA. Here, we report that SMN deficiency severely disrupts local protein synthesis within neuronal growth cones. We also identify the cytoskeleton-associated growth-associated protein 43 (GAP43) mRNA as a new target of SMN and show that motor neurons from SMA mouse models have reduced levels ofGAP43mRNA and protein in axons and growth cones. Importantly, overexpression of two mRNA-binding proteins, HuD and IMP1, restoresGAP43mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate that SMN plays an important role in the localization and local translation of mRNAs with important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA. The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays a key role in assembling RNA/protein complexes that are essential for mRNA splicing. It remains unclear whether defects in this well characterized housekeeping function cause the specific degeneration of spinal motor neurons observed in SMA. Here, we describe an additional role of SMN in regulating the axonal localization and local translation of the mRNA encoding growth-associated protein 43 (GAP43). This study supports a model whereby SMN deficiency impedes transport and local translation of mRNAs important for neurite outgrowth and stabilization

  1. An observational study of implicit motor imagery using laterality recognition of the hand after stroke.

    Science.gov (United States)

    Amesz, Sarah; Tessari, Alessia; Ottoboni, Giovanni; Marsden, Jon

    2016-01-01

    To explore the relationship between laterality recognition after stroke and impairments in attention, 3D object rotation and functional ability. Observational cross-sectional study. Acute care teaching hospital. Thirty-two acute and sub-acute people with stroke and 36 healthy, age-matched controls. Laterality recognition, attention and mental rotation of objects. Within the stroke group, the relationship between laterality recognition and functional ability, neglect, hemianopia and dyspraxia were further explored. People with stroke were significantly less accurate (69% vs 80%) and showed delayed reaction times (3.0 vs 1.9 seconds) when determining the laterality of a pictured hand. Deficits either in accuracy or reaction times were seen in 53% of people with stroke. The accuracy of laterality recognition was associated with reduced functional ability (R(2) = 0.21), less accurate mental rotation of objects (R(2) = 0.20) and dyspraxia (p = 0.03). Implicit motor imagery is affected in a significant number of patients after stroke with these deficits related to lesions to the motor networks as well as other deficits seen after stroke. This research provides new insights into how laterality recognition is related to a number of other deficits after stroke, including the mental rotation of 3D objects, attention and dyspraxia. Further research is required to determine if treatment programmes can improve deficits in laterality recognition and impact functional outcomes after stroke.

  2. Amyotrophic lateral sclerosis – a motor neuron disease. Case report

    Directory of Open Access Journals (Sweden)

    Maja Rubinowicz-Zasada

    2015-03-01

    Full Text Available Amyotrophic lateral sclerosis, also known as Charcot’s disease and motor neuron disease, is a progressive neurodegenerative disease that causes muscle weakness, paralysis, and ultimately, respiratory failure. The aetiology and the pathogenesis of the syndrome remain unknown. Most people live 2–5 years after their first signs of the disease. There is no cure or effective treatment. We present a case of a female patient affected by progressing Charcot’s disease. On the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R, the patient obtained 21 points. Atrophy and muscle spasm were very extended. Electromyography revealed features of coexisting denervation and reinnervation in the examined muscles. A growing number of Charcot’s disease cases require multidirectional actions to meet patient’s physical, emotional, and nutritional needs. Amyotrophic lateral sclerosis is an incurable disease. However, it is possible to relieve its symptoms by applying systematic physical rehabilitation.

  3. Using Brain Oscillations and Corticospinal Excitability to Understand and Predict Post-Stroke Motor Function

    Directory of Open Access Journals (Sweden)

    Aurore Thibaut

    2017-05-01

    Full Text Available What determines motor recovery in stroke is still unknown and finding markers that could predict and improve stroke recovery is a challenge. In this study, we aimed at understanding the neural mechanisms of motor function recovery after stroke using neurophysiological markers by means of cortical excitability (transcranial magnetic stimulation—TMS and brain oscillations (electroencephalography—EEG. In this cross-sectional study, 55 subjects with chronic stroke (62 ± 14 yo, 17 women, 32 ± 42 months post-stroke were recruited in two sites. We analyzed TMS measures (i.e., motor threshold—MT—of the affected and unaffected sides and EEG variables (i.e., power spectrum in different frequency bands and different brain regions of the affected and unaffected hemispheres and their correlation with motor impairment as measured by Fugl-Meyer. Multiple univariate and multivariate linear regression analyses were performed to identify the predictors of good motor function. A significant interaction effect of MT in the affected hemisphere and power in beta bandwidth over the central region for both affected and unaffected hemispheres was found. We identified that motor function positively correlates with beta rhythm over the central region of the unaffected hemisphere, while it negatively correlates with beta rhythm in the affected hemisphere. Our results suggest that cortical activity in the affected and unaffected hemisphere measured by EEG provides new insights on the association between high-frequency rhythms and motor impairment, highlighting the role of an excess of beta in the affected central cortical region in poor motor function in stroke recovery.

  4. Improved motor performance in patients with acute stroke using the optimal individual attentional strategy

    Science.gov (United States)

    Sakurada, Takeshi; Nakajima, Takeshi; Morita, Mitsuya; Hirai, Masahiro; Watanabe, Eiju

    2017-01-01

    It is believed that motor performance improves when individuals direct attention to movement outcome (external focus, EF) rather than to body movement itself (internal focus, IF). However, our previous study found that an optimal individual attentional strategy depended on motor imagery ability. We explored whether the individual motor imagery ability in stroke patients also affected the optimal attentional strategy for motor control. Individual motor imagery ability was determined as either kinesthetic- or visual-dominant by a questionnaire in 28 patients and 28 healthy-controls. Participants then performed a visuomotor task that required tracing a trajectory under three attentional conditions: no instruction (NI), attention to hand movement (IF), or attention to cursor movement (EF). Movement error in the stroke group strongly depended on individual modality dominance of motor imagery. Patients with kinesthetic dominance showed higher motor accuracy under the IF condition but with concomitantly lower velocity. Alternatively, patients with visual dominance showed improvements in both speed and accuracy under the EF condition. These results suggest that the optimal attentional strategy for improving motor accuracy in stroke rehabilitation differs according to the individual dominance of motor imagery. Our findings may contribute to the development of tailor-made pre-assessment and rehabilitation programs optimized for individual cognitive abilities. PMID:28094320

  5. Changes in structural integrity are correlated with motor and functional recovery after post-stroke rehabilitation.

    Science.gov (United States)

    Fan, Yang-teng; Lin, Keh-chung; Liu, Ho-ling; Chen, Yao-liang; Wu, Ching-yi

    2015-01-01

    Diffusion tensor imaging (DTI) studies indicate the structural integrity of the ipsilesional corticospinal tract (CST) and the transcallosal motor tract, which are closely linked to stroke recovery. However, the individual contribution of these 2 fibers on different levels of outcomes remains unclear. Here, we used DTI tractography to investigate whether structural changes of the ipsilesional CST and the transcallosal motor tracts associate with motor and functional recovery after stroke rehabilitation. Ten participants with post-acute stroke underwent the Fugl-Meyer Assessment (FMA), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM), and DTI before and after bilateral robotic training. All participants had marked improvements in motor performance, functional use of the affected arm, and independence in daily activities. Increased fractional anisotropy (FA) in the ipsilesional CST and the transcallosal motor tracts was noted from pre-treatment to the end of treatment. Participants with higher pre-to-post differences in FA values of the transcallosal motor tracts had greater gains in the WMFT and the FIM scores. A greater improvement on the FMA was coupled with increased FA changes along the ipsilesional CST. These findings suggest 2 different structural indicators for post-stroke recovery separately at the impairment-based and function-based levels.

  6. Histological and functional benefit following transplantation of motor neuron progenitors to the injured rat spinal cord.

    Directory of Open Access Journals (Sweden)

    Sharyn L Rossi

    2010-07-01

    Full Text Available Motor neuron loss is characteristic of cervical spinal cord injury (SCI and contributes to functional deficit.In order to investigate the amenability of the injured adult spinal cord to motor neuron differentiation, we transplanted spinal cord injured animals with a high purity population of human motor neuron progenitors (hMNP derived from human embryonic stem cells (hESCs. In vitro, hMNPs displayed characteristic motor neuron-specific markers, a typical electrophysiological profile, functionally innervated human or rodent muscle, and secreted physiologically active growth factors that caused neurite branching and neuronal survival. hMNP transplantation into cervical SCI sites in adult rats resulted in suppression of intracellular signaling pathways associated with SCI pathogenesis, which correlated with greater endogenous neuronal survival and neurite branching. These neurotrophic effects were accompanied by significantly enhanced performance on all parameters of the balance beam task, as compared to controls. Interestingly, hMNP transplantation resulted in survival, differentiation, and site-specific integration of hMNPs distal to the SCI site within ventral horns, but hMNPs near the SCI site reverted to a neuronal progenitor state, suggesting an environmental deficiency for neuronal maturation associated with SCI.These findings underscore the barriers imposed on neuronal differentiation of transplanted cells by the gliogenic nature of the injured spinal cord, and the physiological relevance of transplant-derived neurotrophic support to functional recovery.

  7. Increased serum neuron specific enolase concentrations in patients with hyperglycemic cortical ischemic stroke

    NARCIS (Netherlands)

    Elting, JW; De Keyser, J; Sulter, G.

    1998-01-01

    A detrimental effect of hyperglycemia in ischemic brain has been demonstrated in laboratory experiments and it has been found that hyperglycemia in ischemic stroke is a predictor of poor outcome. We determined serum neuron specific enolase (NSE) concentrations in 41 consecutive patients with a

  8. Ketogenic Diet Provides Neuroprotective Effects against Ischemic Stroke Neuronal Damages

    Directory of Open Access Journals (Sweden)

    Sheida Shaafi

    2014-12-01

    Full Text Available Ischemic stroke is a leading cause of death and disability in the world. Many mechanisms contribute in cell death in ischemic stroke. Ketogenic diet which has been successfully used in the drug-resistant epilepsy has been shown to be effective in many other neurologic disorders. The mechanisms underlying of its effects are not well studied, but it seems that its neuroprotective ability is mediated at least through alleviation of excitotoxicity, oxidative stress and apoptosis events. On the basis of these mechanisms, it is postulated that ketogenic diet could provide benefits to treatment of cerebral ischemic injuries.

  9. The potential dual role of transcallosal inhibition in post-stroke motor recovery.

    Science.gov (United States)

    Bertolucci, Federica; Chisari, Carmelo; Fregni, Felipe

    2018-01-01

    Up to now, the mechanism of motor impairment and recovery after stroke has been thought to be based on the interhemispheric competition model. According to this model, which assumes that suppressing the excitability of contralesional hemisphere will enhance recovery by reducing transcallosal inhibition (TCI) of the stroke hemisphere, many clinical trials used non-invasive brain stimulation to improve motor function. Despite some positive findings, meta-analysis shows an important source of variability in the results, questioning whether the interhemispheric competition model would be exhaustive enough to explain the positive results or whether other mechanisms could explain the motor effects of inhibitory stimulation in the contralesional hemisphere. The goal of this study was to review the relationship between increased TCI and motor impairment after stroke.A systematic review of clinical studies investigating TCI through transcranial magnetic stimulation (TMS) in stroke patients and the relationship of this metric with motor recovery was then performed. After a literary search in PubMed eleven articles were included. The potential role of several covariates was examined and discussed.Overall, the importance of TCI as a putative mechanism for stimulation of the contralesional hemisphere seems to depend on the baseline motor function. In other words, from evidence coming mostly from chronic patients, modulation of abnormal TCI seems to be useful for patients with good motor function and less important in patients with poor motor function. TCI seems to be negatively correlated with mirror movements of the paretic hand. It can be inferred that suppressing the activity of the contralesional hemisphere could be beneficial for patients with good residual motor function and strong TCI, but not for those with poor motor function and weak TCI. Baseline motor function and measure of TCI should be taken into account for stratification of patients in clinical trials and for

  10. Respiratory management of motor neurone disease: a review of current practice and new developments.

    Science.gov (United States)

    Rafiq, Muhammad Khizar; Proctor, Alison Ruth; McDermott, Christopher J; Shaw, Pamela J

    2012-06-01

    Motor neurone disease is a neurodegenerative condition with a significant morbidity and shortened life expectancy. Hypoventilatory respiratory failure is the most common cause of death and respiratory function significantly predicts both survival and quality of life in patients with motor neurone disease. Accordingly, supporting and maintaining respiratory function is important in caring for these patients. The most significant advance in motor neurone disease care of recent years has been the domiciliary provision of non-invasive ventilation for treating respiratory failure. Neuromuscular respiratory weakness also leads to ineffective cough and retained airways secretions, predisposing to recurrent chest infections. In this review, we discuss current practice and recent developments in the respiratory management of motor neurone disease, in terms of ventilatory support and cough augmentation.

  11. MotomiRs: miRNAs in Motor Neuron Function and Disease.

    Science.gov (United States)

    Hawley, Zachary C E; Campos-Melo, Danae; Droppelmann, Cristian A; Strong, Michael J

    2017-01-01

    MiRNAs are key regulators of the mammalian transcriptome that have been increasingly linked to degenerative diseases of the motor neurons. Although many of the miRNAs currently incriminated as participants in the pathogenesis of these diseases are also important to the normal development and function of motor neurons, at present there is no knowledge of the complete miRNA profile of motor neurons. In this review, we examine the current understanding with respect to miRNAs that are specifically required for motor neuron development, function and viability, and provide evidence that these should be considered as a functional network of miRNAs which we have collectively termed MotomiRs. We will also summarize those MotomiRs currently known to be associated with both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), and discuss their potential use as biomarkers.

  12. Joining forces: Motor control meets mirror neurons. Comment on "Grasping synergies: A motor-control approach to the mirror neuron mechanism" by D'Ausilio, Bartoli, and Maffongelli

    Science.gov (United States)

    Casile, Antonino

    2015-03-01

    Several consistent and compelling experimental findings suggest that in primates the observation of actions or movements activates the observer's motor cortex (for a recent and very thorough review see [1]). One important piece of evidence was the discovery of mirror neurons, that are neurons in the macaque ventral pre-motor (area F5), motor and parietal cortices (area PFG) that respond both when the monkey executes a goal-directed motor act (e.g. breaking a peanut) or when it sees a similar action executed by others [2-5]. A similar system has been later reported also in humans ([6-8] but see also [9,10] for negative results).

  13. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients

    Directory of Open Access Journals (Sweden)

    Meng-Lu Liu

    2016-01-01

    Full Text Available Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS. Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

  14. Stroke Survivors Scoring Zero on the NIH Stroke Scale Score Still Exhibit Significant Motor Impairment and Functional Limitation

    Directory of Open Access Journals (Sweden)

    Brittany Hand

    2014-01-01

    Full Text Available Objective. To determine the National Institutes of Health Stroke Scale’s (NIHSS’s association with upper extremity (UE impairment and functional outcomes. Design. Secondary, retrospective analysis of randomized controlled trial data. Setting. Not applicable. Participants. 146 subjects with stable, chronic stroke-induced hemiparesis. Intervention. The NIHSS, the UE Fugl-Meyer (FM, and the Arm Motor Ability Test (AMAT were administered prior to their participation in a multicenter randomized controlled trial. Main Outcome Measures. The NIHSS, FM, and AMAT. Results. The association between the NIHSS and UE impairment was statistically significant (P=-0.204;p=0.014 but explained less than 4% of the variance among UE FM scores. The association between NIHSS total score and function as measured by the AMAT was not statistically significant (P=-0.141;p=0.089. Subjects scoring a “zero” on the NIHSS exhibited discernible UE motor deficits and varied scores on the UE FM and AMAT. Conclusion. While being used in stroke trials, the NIHSS may have limited ability to discriminate between treatment responses, even when only a relatively narrow array of impairment levels exists among patients. Given these findings, NIHSS use should be restricted to acute stroke studies and clinical settings with the goal of reporting stroke severity.

  15. Stroke Survivors Scoring Zero on the NIH Stroke Scale Score Still Exhibit Significant Motor Impairment and Functional Limitation.

    Science.gov (United States)

    Hand, Brittany; Page, Stephen J; White, Susan

    2014-01-01

    Objective. To determine the National Institutes of Health Stroke Scale's (NIHSS's) association with upper extremity (UE) impairment and functional outcomes. Design. Secondary, retrospective analysis of randomized controlled trial data. Setting. Not applicable. Participants. 146 subjects with stable, chronic stroke-induced hemiparesis. Intervention. The NIHSS, the UE Fugl-Meyer (FM), and the Arm Motor Ability Test (AMAT) were administered prior to their participation in a multicenter randomized controlled trial. Main Outcome Measures. The NIHSS, FM, and AMAT. Results. The association between the NIHSS and UE impairment was statistically significant (P = -0.204; p = 0.014) but explained less than 4% of the variance among UE FM scores. The association between NIHSS total score and function as measured by the AMAT was not statistically significant (P = -0.141; p = 0.089). Subjects scoring a "zero" on the NIHSS exhibited discernible UE motor deficits and varied scores on the UE FM and AMAT. Conclusion. While being used in stroke trials, the NIHSS may have limited ability to discriminate between treatment responses, even when only a relatively narrow array of impairment levels exists among patients. Given these findings, NIHSS use should be restricted to acute stroke studies and clinical settings with the goal of reporting stroke severity.

  16. Lower-limb motor coordination is significantly impaired in ambulatory people with chronic stroke: A cross-sectional study.

    Science.gov (United States)

    Menezes, Kênia K P; Nascimento, Lucas R; Pinheiro, Marina B; Scianni, Aline A; Faria, Christina D C M; Avelino, Patrick R; Faria-Fortini, Iza; Teixeira-Salmela, Luci F

    2017-04-06

    To establish the deficits of motor coordination of the lower limbs after stroke, in comparison with healthy controls, and to investigate whether the magnitude of the deficits would be influenced by the levels of motor recovery. Cross-sectional study. Chronic stroke patients and healthy subjects. Lower-limb motor coordination of both stroke and healthy volunteers was measured using the Lower Extremity Motor Coordination Test (LEMOCOT). The motor coordination deficits of the participants with stroke were analysed all together and separated, according to their levels of motor recovery, measured using the Fugl-Meyer lower-limb motor section scores. Ninety-seven individuals with chronic stroke, 55 men, mean age 58 years, were evaluated. Motor coordination was significantly impaired on both paretic (mean: -22 touches; 95% confidence interval (95% CI) -24 to -19; deficit: 61%) and non-paretic (mean -6 touches; 95% CI -8 to -4; deficit: 17%) lower limbs. Significant differences in the LEMOCOT scores were found between the levels of motor recovery (p Motor coordination of the lower limbs is significantly impaired after stroke, but the deficits of the non-paretic lower limb (17%) appear not to be clinically relevant. These findings suggest that interventions prescribed to improve motor coordination after stroke should focus on the paretic lower limb and/or include bilateral activities.

  17. Modeling Protein Aggregation and the Heat Shock Response in ALS iPSC-Derived Motor Neurons.

    Science.gov (United States)

    Seminary, Emily R; Sison, Samantha L; Ebert, Allison D

    2018-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in C9orf72, SOD1 , or TDP-43 are the most common causes of familial ALS, together responsible for at least 60% of these cases. Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62. These inclusions are normally prevented and cleared by heat shock proteins (Hsps), suggesting that ALS motor neurons have an impaired ability to induce the heat shock response (HSR). Accordingly, there is evidence of decreased induction of Hsps in ALS mouse models and in human post-mortem samples compared to unaffected controls. However, the role of Hsps in protein accumulation in human motor neurons has not been fully elucidated. Here, we generated motor neuron cultures from human induced pluripotent stem cell (iPSC) lines carrying mutations in SOD1, TDP-43 , or C9orf72 . In this study, we provide evidence that despite a lack of overt motor neuron loss, there is an accumulation of insoluble, aggregation-prone proteins in iPSC-derived motor neuron cultures but that content and levels vary with genetic background. Additionally, although iPSC-derived motor neurons are generally capable of inducing the HSR when exposed to a heat stress, protein aggregation itself is not sufficient to induce the HSR or stress granule formation. We therefore conclude that ALS iPSC-derived motor neurons recapitulate key early pathological features of the disease and fail to endogenously upregulate the HSR in response to increased protein burden.

  18. Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death.

    Science.gov (United States)

    Nichols, Nicole L; Craig, Taylor A; Tanner, Miles A

    2017-08-16

    Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1 G93A ), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1 G93A rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28days following bilateral intrapleural injections of: 1) CTB-SAP (25μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162±18%, n=8 vs. 63±3%; n=8; p0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Rehabilitation of motor function after stroke: a multiple systematic review focused on techniques to stimulate upper extremity recovery

    Directory of Open Access Journals (Sweden)

    Samar M Hatem

    2016-09-01

    Full Text Available Stroke is one of the leading causes for disability worldwide. Motor function deficits due to stroke affect the patients’ mobility, their limitation in daily life activities, their participation in society and their odds of returning to professional activities. All of these factors contribute to a low overall quality of life. Rehabilitation training is the most effective way to reduce motor impairments in stroke patients. This multiple systematic review focuses both on standard treatment methods and on innovating rehabilitation techniques used to promote upper extremity motor function in stroke patients. A total number of 5712 publications on stroke rehabilitation was systematically reviewed for relevance and quality with regards to upper extremity motor outcome. This procedure yielded 270 publications corresponding to the inclusion criteria of the systematic review. Recent technology-based interventions in stroke rehabilitation including non-invasive brain stimulation, robot-assisted training and virtual reality immersion are addressed. Finally, a decisional tree based on evidence from the literature and characteristics of stroke patients is proposed.At present, the stroke rehabilitation field faces the challenge to tailor evidence-based treatment strategies to the needs of the individual stroke patient. Interventions can be combined in order to achieve the maximal motor function recovery for each patient. Though the efficacy of some interventions may be under debate, motor skill learning and some new technological approaches give promising outcome prognosis in stroke motor rehabilitation.

  20. Rehabilitation of Motor Function after Stroke: A Multiple Systematic Review Focused on Techniques to Stimulate Upper Extremity Recovery

    Science.gov (United States)

    Hatem, Samar M.; Saussez, Geoffroy; della Faille, Margaux; Prist, Vincent; Zhang, Xue; Dispa, Delphine; Bleyenheuft, Yannick

    2016-01-01

    Stroke is one of the leading causes for disability worldwide. Motor function deficits due to stroke affect the patients' mobility, their limitation in daily life activities, their participation in society and their odds of returning to professional activities. All of these factors contribute to a low overall quality of life. Rehabilitation training is the most effective way to reduce motor impairments in stroke patients. This multiple systematic review focuses both on standard treatment methods and on innovating rehabilitation techniques used to promote upper extremity motor function in stroke patients. A total number of 5712 publications on stroke rehabilitation was systematically reviewed for relevance and quality with regards to upper extremity motor outcome. This procedure yielded 270 publications corresponding to the inclusion criteria of the systematic review. Recent technology-based interventions in stroke rehabilitation including non-invasive brain stimulation, robot-assisted training, and virtual reality immersion are addressed. Finally, a decisional tree based on evidence from the literature and characteristics of stroke patients is proposed. At present, the stroke rehabilitation field faces the challenge to tailor evidence-based treatment strategies to the needs of the individual stroke patient. Interventions can be combined in order to achieve the maximal motor function recovery for each patient. Though the efficacy of some interventions may be under debate, motor skill learning, and some new technological approaches give promising outcome prognosis in stroke motor rehabilitation. PMID:27679565

  1. Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model

    DEFF Research Database (Denmark)

    Dahlke, Carolin; Saberi, Darius; Ott, Bastian

    2015-01-01

    Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the upper and lower motor neurons, characterized by rapid progressive weakness, muscle atrophy, dysarthria, dysphagia, and dyspnea. Whereas the exact cause of ALS remains uncertain, the wobbler mouse (phenotype...... WR; genotype wr/wr) equally develops a progressive degeneration of motor neurons in the spinal cord and motor cortex with striking similarities to sporadic human ALS, suggesting the possibility of a common pathway to cell death. Methods With the aid of immunohistochemistry, confocal laser scanning...... microscopy, and transmission electron microscopy techniques, we analyze the proliferation behavior of microglial cells and astrocytes. We also investigate possible motor neuron death in the mouse motor cortex at different stages of the wobbler disease, which so far has not received much attention. Results...

  2. Combined pharmacological and motor training interventions for recovery of upper limb function in subacute ischemic stroke

    Directory of Open Access Journals (Sweden)

    Ioana Stanescu

    2017-05-01

    Full Text Available Motor deficit, especially in the upper limb, is the primary contributor in post-stroke disability. Recovery of motor function relies on neural plasticity – cortical plastic reorganization – a spontaneous process, which could be enhanced from early phases by rehabilitative strategies. The subacute stage after stroke is the critical period during which the brain is most receptive to rehabilitation strategies. Based on the recent results of 2 trials in stroke rehabilitation using pharmacological intervention with Cerebrolysin in combination with standardized kinesitherapy, we conducted a pilot study of 4 consecutive patients with acute ischemic stroke, treated with Cerebrolysin for 28 days after stroke, and with intensive task-specific kinesitherapy from day 7 to day 28 after stroke. We assessed stroke severity with NIHSS score, upper limb function with ARAT (Action Research Arm Test score, disability with modified Rankin scale and patient’s autonomy with Barthel Index, at day 0 and day 30 after stroke. After 28 days of combined therapy all 4 patients improved, most significant improvement was seen in upper limb function, measured by ARAT score and in autonomy measured by Barthel Index.

  3. Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy.

    Science.gov (United States)

    Simon, Christian M; Dai, Ya; Van Alstyne, Meaghan; Koutsioumpa, Charalampia; Pagiazitis, John G; Chalif, Joshua I; Wang, Xiaojian; Rabinowitz, Joseph E; Henderson, Christopher E; Pellizzoni, Livio; Mentis, George Z

    2017-12-26

    The hallmark of spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  4. Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

    Science.gov (United States)

    Fournier, Christina N; Murphy, Alyssa; Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

    2016-03-01

    The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

  5. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    Science.gov (United States)

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches.

  6. Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

    Directory of Open Access Journals (Sweden)

    Brian J. Wainger

    2014-04-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1, C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.

  7. Sleep Parameters, Functional Status, and Time Post-Stroke are Associated with Offline Motor Skill Learning in People with Chronic Stroke.

    Science.gov (United States)

    Siengsukon, Catherine; Al-Dughmi, Mayis; Al-Sharman, Alham; Stevens, Suzanne

    2015-01-01

    Mounting evidence demonstrates that individuals with stroke benefit from sleep to enhance learning of a motor task. While stage NREM2 sleep and REM sleep have been associated with offline motor skill learning in neurologically intact individuals, it remains unknown which sleep parameters or specific sleep stages are associated with offline motor skill learning in individuals with stroke. Twenty individuals with chronic stroke (>6 months following stroke) and 10 control participants slept for three consecutive nights in a sleep laboratory with polysomnography. Participants practiced a tracking task the morning before the third night and underwent a retention test the morning following the third night. Offline learning on the tracking task was assessed. Pearson's correlations assessed for associations between the magnitude of offline learning and sleep variables, age, upper-extremity motor function, stroke severity, depression, and time since stroke occurrence. Individuals with stroke performed with significantly less error on the tracking task following a night of sleep (p = 0.006) while the control participants did not (p = 0.816). Increased sleep efficiency (r = -0.285), less time spent in stage NREM3 sleep (r = 0.260), and more time spent in stage REM sleep (r = -0.266) were weakly-to-moderately associated with increased magnitude of offline motor learning. Furthermore, higher upper-extremity motor function (r = -0.400), lower stroke severity (r = 0.360), and less time since stroke occurrence (r = 0.311) were moderately associated with increased magnitude of offline motor learning. This study is the first study to provide insight into which sleep stages and individual characteristics may be associated with offline learning in people with stroke. Further research is needed to delineate which factors or combination of factors promote offline motor learning in people with neurologic injury to best promote motor recovery in these

  8. Sleep parameters, functional status and time post-stroke are associated with off-line motor skill learning in people with chronic stroke

    Directory of Open Access Journals (Sweden)

    Catherine eSiengsukon

    2015-10-01

    Full Text Available Background: Mounting evidence demonstrates that individuals with stroke benefit from sleep to enhance learning of a motor task. While stage NREM2 sleep and REM sleep have been associated with off-line motor skill learning in neurologically-intact individuals, it remains unknown which sleep parameters or specific sleep stages are associated with off-line motor skill learning in individuals with stroke. Methods: Twenty individuals with chronic stroke (> 6 months following stroke and 10 neurologically slept for three consecutive nights in a sleep laboratory with polysomnography. Participants practiced a tracking task the morning before the third night and underwent a retention test the morning following the third night. Off-line learning on the tracking task was assessed. Pearson’s correlations assessed for associations between the magnitude of off-line learning and sleep variables, age, upper extremity motor function, stroke severity, depression and time since stroke occurrence.Results: Individuals with stroke performed with significantly less error on the tracking task following a night of sleep (p=.006 while the control participants did not (p=.816. Increased sleep efficiency (r= -.285, less time spent in stage NREM3 sleep (r=.260, and more time spent in stage REM sleep (r= -.266 was weakly-to-moderately associated with increased magnitude of off-line motor learning. Furthermore, higher upper-extremity motor function (r = -.400, lower stroke severity (r = .360, and less time since stroke occurrence (r=.311 were moderately associated with increased magnitude of off-line motor learning. Conclusion: This study is the first study to provide insight into which sleep stages and individual characteristics may be associated with off-line learning in people with stroke. Future work should continue to understand which factors or combination of factors promote off-line motor learning in people with neurologic injury to best promote motor recovery in

  9. BDNF genotype interacts with motor-function to influence rehabilitation responsiveness post-stroke

    Directory of Open Access Journals (Sweden)

    Christine T Shiner

    2016-05-01

    Full Text Available Background. Persistent motor impairment is common but highly heterogeneous post-stroke. Genetic polymorphisms, including those identified on the brain derived neurotrophic factor (BDNF and apolipoprotein E (APOE genes, may contribute to this variability by limiting the capacity for use-dependent neuroplasticity, and hence rehabilitation responsiveness.Objective. To determine whether BDNF and APOE genotypes influence motor improvement facilitated by post-stroke upper-limb rehabilitation. Methods. BDNF Val66Met and APOE isoform genotypes were determined using leukocyte DNA for 55 community-dwelling patients 2-123 months post-stroke. All patients completed a dose-matched upper-limb rehabilitation program of either Wii-based Movement Therapy or Constraint-induced Movement Therapy. Upper-limb motor-function was assessed pre- and post-therapy using a suite of functional measures. Results. Motor-function improved for all patients post-therapy, with no difference between therapy groups. In the pooled data, there was no significant effect of BDNF or APOE genotype on motor-function at baseline, or following the intervention. However, a significant interaction between the level of residual motor-function and BDNF genotype was identified (p=0.029, whereby post-therapy improvement was significantly less for Met allele carriers with moderate and high, but not low motor-function. There was no significant association between APOE genotype and therapy outcomes. Conclusions. This study identified a novel interaction between the BDNF Val66Met polymorphism, motor-function status and the magnitude of improvement with rehabilitation in chronic stroke. This polymorphism does not preclude, but may reduce, the magnitude of motor improvement with therapy, particularly for patients with higher but not lower residual motor-function. BDNF genotype should be considered in the design and interpretation of clinical trials.

  10. Farming and incidence of motor neuron disease: French nationwide study.

    Science.gov (United States)

    Kab, S; Moisan, F; Elbaz, A

    2017-09-01

    The association of farming with motor neuron disease (MND) is unclear, with conflicting studies. We performed a French nationwide study of the association of farming with MND incidence, and compared findings with those for Parkinson's disease (PD), which has been shown to be more frequent in farmers. We used the French national health insurance and hospital discharge databases to identify MND/PD incident cases. The Mutualité Sociale Agricole (MSA) guarantees health insurance for farmers and agricultural workers. We compared the incidence of MND (2010-2014) and PD (2011-2012) in MSA farmers, MSA workers and non-MSA affiliates, and estimated relative risks (RRs) and 95% confidence intervals (CIs). Probabilistic sensitivity analyses were used for external smoking adjustment. Analyses relied on 8931 MND (MSA, 9%) and 45 409 PD (MSA,11%) cases. There was a trend towards higher MND incidence in MSA farmers compared with non-MSA affiliates (RR,1.08; 95% CI,0.99-1.18) and MSA workers (RR, 1.13; 95% CI, 0.97-1.31) that strengthened after smoking adjustment (if associated with MND). PD incidence was higher in MSA farmers than non-MSA affiliates (RR, 1.13; 95% CI, 1.08-1.17) and MSA workers (RR, 1.10; 95% CI, 1.02-1.18); this association remained after smoking adjustment (RR, 1.09; 95% CI, 1.05-1.14). This French nationwide study suggested an association between farming and MND, and confirmed higher PD incidence in farmers in France, a country with high pesticide use. © 2017 EAN.

  11. Single photon emission computed tomography in motor neuron disease with dementia.

    Science.gov (United States)

    Sawada, H; Udaka, F; Kishi, Y; Seriu, N; Mezaki, T; Kameyama, M; Honda, M; Tomonobu, M

    1988-01-01

    Single photon emission computed tomography with [123 I] isopropylamphetamine was carried out on a patient with motor neuron disease with dementia. [123 I] uptake was decreased in the frontal lobes. This would reflect the histopathological findings such as neuronal loss and gliosis in the frontal lobes.

  12. On-line 'automatic pilot' training for hand and arm motor rehabilitation after stroke.

    Science.gov (United States)

    Zeng, Jinhua; Sun, Yaoru; Jiang, Li

    2011-02-01

    As stroke being one of the most leading causes of death worldwide, even stroke survivors have to suffer from dysfunctions of limb controls and inabilities of speech or vision. Cognitive neuroscientists have found various forms of automatic behaviours in healthy people, which generally cover motor components of upper limbs and are essential for coordination and mobility relevant activities. Meanwhile, the robot-assisted therapy and functional electrical stimulation have become prominent rehabilitation techniques for patients' rehabilitation after stroke. With the integration of robot-aided therapeutic systems and the functional electrical stimulation, the on-line 'automatic pilot' training of the visual inspired stimulation for upper limbs can offer a feasible treatment for patients after stroke to recover motor performance. Copyright © 2010 Elsevier Ltd. All rights reserved.

  13. Virtual Reality Rehabilitation from Social Cognitive and Motor Learning Theoretical Perspectives in Stroke Population

    OpenAIRE

    Imam, Bita; Jarus, Tal

    2014-01-01

    Objectives. To identify the virtual reality (VR) interventions used for the lower extremity rehabilitation in stroke population and to explain their underlying training mechanisms using Social Cognitive (SCT) and Motor Learning (MLT) theoretical frameworks. Methods. Medline, Embase, Cinahl, and Cochrane databases were searched up to July 11, 2013. Randomized controlled trials that included a VR intervention for lower extremity rehabilitation in stroke population were included. The Physiothera...

  14. Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression.

    Science.gov (United States)

    Kerk, Sze Yen; Kratsios, Paschalis; Hart, Michael; Mourao, Romulo; Hobert, Oliver

    2017-01-04

    A common organizational feature of nervous systems is the existence of groups of neurons that share common traits but can be divided into individual subtypes based on anatomical or molecular features. We elucidate the mechanistic basis of neuronal diversification processes in the context of C.elegans ventral cord motor neurons that share common traits that are directly activated by the terminal selector UNC-3. Diversification of motor neurons into different classes, each characterized by unique patterns of effector gene expression, is controlled by distinct combinations of phylogenetically conserved, class-specific transcriptional repressors. These repressors are continuously required in postmitotic neurons to prevent UNC-3, which is active in all neuron classes, from activating class-specific effector genes in specific motor neuron subsets via discrete cis-regulatory elements. The strategy of antagonizing the activity of broadly acting terminal selectors of neuron identity in a subtype-specific fashion may constitute a general principle of neuron subtype diversification. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Dose-response relationship of robot-assisted stroke motor rehabilitation: the impact of initial motor status.

    Science.gov (United States)

    Hsieh, Yu-wei; Wu, Ching-yi; Lin, Keh-chung; Yao, Grace; Wu, Kuen-yuh; Chang, Ya-ju

    2012-10-01

    The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose-response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits. Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale. The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (P=0.003 and P=0.02) and at posttreatment (P=0.04 and P=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT. This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00917605.

  16. A functional tracking task to assess frontal plane motor control in post stroke gait.

    Science.gov (United States)

    Reissman, Megan E; Dhaher, Yasin Y

    2015-07-16

    The ability to execute appropriate medio-lateral foot placements during gait is thought to require active frontal plane control and to be critical in maintaining upright posture during gait. The aggregate frontal plane metrics of step width and step width variability have been assessed for post-stroke populations, but only under normal walking conditions. However, in the case of stroke, limb specific differences in sensory-motor control are likely. Thus, an investigation of limb specific motor control characteristics under tracking task conditions is needed to appropriately characterize frontal plane sensory-motor control post-stroke. Chronic stroke subjects (n=15) and age matched control subjects (n=10) tracked static, bilateral foot placement targets at self-selected walking speeds and completed a free walking trial. Variability and error of tracking performance were analyzed for step width and foot placement. Stroke subjects demonstrated reduced ability to control step width variability and foot placement variability, compared to control subjects. Step width variability and affected limb foot placement variability were sensitive to task complexity, increasing significantly in response to a decrease in step width target size. These results show that stroke mediated changes in the sensory-motor integration processes are manifested as inter-limb differences in frontal plane motor variability during a gait tracking task, with an additional sensitivity to task complexity. Additionally, the proposed step width tracking paradigm presents a clinically reproducible motor control metric that can be used for diagnostic assessment or as a potential outcome for a gait training regimen. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Statins Promote Long-Term Recovery after Ischemic Stroke by Reconnecting Noradrenergic Neuronal Circuitry

    Directory of Open Access Journals (Sweden)

    Kyoung Joo Cho

    2015-01-01

    Full Text Available Inhibitors of HMG-CoA reductase (statins, widely used to lower cholesterol in coronary heart and vascular disease, are effective drugs in reducing the risk of stroke and improving its outcome in the long term. After ischemic stroke, cardiac autonomic dysfunction and psychological problems are common complications related to deficits in the noradrenergic (NA system. This study investigated the effects of statins on the recovery of NA neuron circuitry and its function after transient focal cerebral ischemia (tFCI. Using the wheat germ agglutinin (WGA transgene technique combined with the recombinant adenoviral vector system, NA-specific neuronal pathways were labeled, and were identified in the locus coeruleus (LC, where NA neurons originate. NA circuitry in the atorvastatin-treated group recovered faster than in the vehicle-treated group. The damaged NA circuitry was partly reorganized with the gradual recovery of autonomic dysfunction and neurobehavioral deficit. Newly proliferated cells might contribute to reorganizing NA neurons and lead anatomic and functional recovery of NA neurons. Statins may be implicated to play facilitating roles in the recovery of the NA neuron and its function.

  18. Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.

    Science.gov (United States)

    Jaiswal, Manoj Kumar

    2017-05-01

    Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro " disease in dish " and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

  19. Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Jaiswal

    2017-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS and motor neuron diseases (MNDs are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs, brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs, muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for thefirst time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

  20. Motor Nerve Arborization Requires Proteolytic Domain of Damage-Induced Neuronal Endopeptidase (DINE) during Development.

    Science.gov (United States)

    Matsumoto, Sakiko; Kiryu-Seo, Sumiko; Kiyama, Hiroshi

    2016-04-27

    Damage-induced neuronal endopeptidase (DINE)/endothelin-converting enzyme-like 1 (ECEL1) is a membrane-bound metalloprotease, which we originally identified as a nerve regeneration-associated molecule. Abundant expression of DINE is observed in regenerating neurons, as well as in developing spinal motor neurons. In line with this, DINE-deficient (DINE KO) embryos fail to arborize phrenic motor nerves in the diaphragm and to form proper neuromuscular junctions (NMJ), which lead to death shortly after birth. However, it is unclear whether protease activity of DINE is involved in motor nerve terminal arborization and how DINE participates in the process. To address these issues, we performed an in vivo rescue experiment in which three types of motor-neuron specific DINE transgenic mice were crossed with DINE KO mice. The DINE KO mice, which overexpressed wild-type DINE in motor neurons, succeeded in rescuing the aberrant nerve terminal arborization and lethality after birth, while those overexpressing two types of protease domain-mutated DINE failed. Further histochemical analysis showed abnormal behavior of immature Schwann cells along the DINE-deficient axons. Coculture experiments of motor neurons and Schwann cells ensured that the protease domain of neuronal DINE was required for proper alignment of immature Schwann cells along the axon. These findings suggest that protease activity of DINE is crucial for intramuscular innervation of motor nerves and subsequent NMJ formation, as well as proper control of interactions between axons and immature Schwann cells. Damage-induced neuronal endopeptidase (DINE) is a membrane-bound metalloprotease; expression is abundant in developing spinal motor neurons, as well as in nerve-injured neurons. DINE-deficient (KO) embryos fail to arborize phrenic motor nerves in the diaphragm and to form a neuromuscular junction, leading to death immediately after birth. To address whether proteolytic activity of DINE is involved in this

  1. Lateralization of Motor Cortex Excitability in Stroke Patients during Action Observation: A TMS Study

    Directory of Open Access Journals (Sweden)

    Mattia Marangon

    2014-01-01

    Full Text Available Action observation activates the same motor areas as those involved in the performance of the observed actions and promotes functional recovery following stroke. Movement observation is now considered a promising tool for motor rehabilitation, by allowing patients to train their motor functions when voluntary movement is partially impaired. We asked chronic-stroke patients, affected by either left (LHD or right hemisphere (RHD lesions, to observe either a left or right hand, while grasping a small target (eliciting a precision grip or a large target (eliciting a whole hand grasp directed towards a target object. To better understand the effects of action observation on damaged motor circuits, we used transcranial magnetic stimulation (TMS to induce motor evoked potentials (MEP from two muscles of the unaffected hand in 10 completely hemiplegic participants. Results revealed that LHD patients showed MEP facilitation on the right (contralesional M1 during action observation of hand-object interactions. In contrast, results showed no facilitation of the left (contralesional M1 in RHD patients. Our results confirm that action observation might have a positive influence on the recovery of motor functions after stroke. Activating the motor system by means of action observation might provide a mechanism for improving function, at least in LHD patients.

  2. Transplantation of Xenopus laevis tissues to determine the ability of motor neurons to acquire a novel target.

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    Karen L Elliott

    Full Text Available The evolutionary origin of novelties is a central problem in biology. At a cellular level this requires, for example, molecularly resolving how brainstem motor neurons change their innervation target from muscle fibers (branchial motor neurons to neural crest-derived ganglia (visceral motor neurons or ear-derived hair cells (inner ear and lateral line efferent neurons. Transplantation of various tissues into the path of motor neuron axons could determine the ability of any motor neuron to innervate a novel target. Several tissues that receive direct, indirect, or no motor innervation were transplanted into the path of different motor neuron populations in Xenopus laevis embryos. Ears, somites, hearts, and lungs were transplanted to the orbit, replacing the eye. Jaw and eye muscle were transplanted to the trunk, replacing a somite. Applications of lipophilic dyes and immunohistochemistry to reveal motor neuron axon terminals were used. The ear, but not somite-derived muscle, heart, or liver, received motor neuron axons via the oculomotor or trochlear nerves. Somite-derived muscle tissue was innervated, likely by the hypoglossal nerve, when replacing the ear. In contrast to our previous report on ear innervation by spinal motor neurons, none of the tissues (eye or jaw muscle was innervated when transplanted to the trunk. Taken together, these results suggest that there is some plasticity inherent to motor innervation, but not every motor neuron can become an efferent to any target that normally receives motor input. The only tissue among our samples that can be innervated by all motor neurons tested is the ear. We suggest some possible, testable molecular suggestions for this apparent uniqueness.

  3. Incremental Adaptive Fuzzy Control for Sensorless Stroke Control of A Halbach-type Linear Oscillatory Motor

    Science.gov (United States)

    Lei, Meizhen; Wang, Liqiang

    2018-01-01

    The halbach-type linear oscillatory motor (HT-LOM) is multi-variable, highly coupled, nonlinear and uncertain, and difficult to get a satisfied result by conventional PID control. An incremental adaptive fuzzy controller (IAFC) for stroke tracking was presented, which combined the merits of PID control, the fuzzy inference mechanism and the adaptive algorithm. The integral-operation is added to the conventional fuzzy control algorithm. The fuzzy scale factor can be online tuned according to the load force and stroke command. The simulation results indicate that the proposed control scheme can achieve satisfied stroke tracking performance and is robust with respect to parameter variations and external disturbance.

  4. Maintenance of motor neuron progenitors in Xenopus requires a novel localized cyclin.

    Science.gov (United States)

    Chen, Jun-An; Chu, Sin-Tak; Amaya, Enrique

    2007-03-01

    The ventral spinal cord contains a pool of motor neuron progenitors (pMNs), which sequentially generate motor neurons and oligodendrocytes in the embryo. The mechanisms responsible for the maintenance of pMNs are not clearly understood. We have identified a novel cyclin, cyclin Dx (ccndx), which is specifically expressed in pMNs in Xenopus. Here, we show that inhibition of ccndx causes paralysis in embryos. Furthermore, we show that maintenance of pMNs requires ccndx function. In addition, inhibition of ccndx results in the specific loss of differentiated motor neurons. However, the expression of interneuron or sensory neuron markers is unaffected in these embryos, suggesting that the role of ccndx is specifically to maintain pMNs. Thus, we have identified, for the first time, a tissue-specific cell-cycle regulator that is essential for the maintenance of a pool of neural progenitors in the vertebrate spinal cord.

  5. Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury

    DEFF Research Database (Denmark)

    Ryge, J.; Winther, Ole; Wienecke, J.

    2010-01-01

    Background: Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence...... of modulatory inputs from the brain correlates with the development of spasticity. Results: Here we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use...... a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time...

  6. Mental Practice Combined with Motor Rehabilitation to Treat Upper Limb Hemiparesis of Post-Stroke Patients: Clinical and Experimental Evidence

    Science.gov (United States)

    Machado, Sergio; Lattari, Eduardo; Paes, Flávia; Rocha, Nuno B.F.; Nardi, Antonio E.; Arias-Carrión, Oscar; Mura, Gioia; Yuan, Ti-Fei; Carta, Mauro G.; Campos, Carlos

    2016-01-01

    Stroke is one of the major causes of disability in the world. Due to the extended lifetime of the world's population, the number of people affected by stroke has increased substantially over the last years. Stroke may lead to sensorimotor deficits, usually causing hemiplegia or hemiparesia. In order to reduce motor deficits and accelerate functional recovery, MP combined with motor rehabilitation was introduced to the rehabilitation process of post-stroke patients. Evidence has shown that MP combining with motor rehabilitation based on activities of daily living was more effective than conventional motor rehabilitation used per se. This combination proved very useful and effective, with significant results in improvement of motor deficits in post-stroke patients. However, further studies must be conducted to determine specific parameters, such as type of imagery, frequency or duration. PMID:27346996

  7. Correlation between serum neuron specific enolase and functional neurological outcome in patients of acute ischemic stroke.

    Science.gov (United States)

    Zaheer, Sana; Beg, Mujahid; Rizvi, Imran; Islam, Najmul; Ullah, Ekram; Akhtar, Nishat

    2013-10-01

    The use of biomarkers to predict stroke prognosis is gaining particular attention nowadays. Neuron specific enolase (NSE), which is a dimeric isoenzyme of the glycolytic enzyme enolase and is found mainly in the neurons is one such biomarker. This study was carried out on patients of acute ischemic stroke with the aims to determine the correlation between NSE levels on the day of admission with infarct volume, stroke severity, and functional neurological outcome on day 30. Seventy five patients of acute ischemic stroke admitted in the Department of Medicine were included in the study. Levels of NSE were determined on day 1 using the human NSE ELISA kit (Alpha Diagnostic International Texas 78244, USA). Volume of infarct was measured by computed tomography (CT) scan using the preinstalled software Syngo (version A40A) of Siemen's medical solutions (Forchheim, Germany). Stroke severity at admission was assessed using Glasgow coma scale (GCS) and functional neurological outcome was assessed using modified Rankin scale (mRS) on day 30. Statistical analysis was performed using the SPSS software for windows version 15.0 (SPSS). A positive correlation was found between concentration of NSE on day 1 and infarct volume determined by CT scan (r = 0.955, P < 0.001). A strong negative correlation was found between GCS at presentation and concentration of NSE on day 1 (r = -0.806, P < 0.001). There was a positive correlation between NSE levels at day 1 and functional neurological outcome assessed by mRS at day 30 (r = 0.744, P < 0.001). Serum levels of NSE in first few days of ischemic stroke can serve as a useful marker to predict stroke severity and early functional outcome. However, larger studies with serial estimation of NSE are needed to establish these observations more firmly.

  8. Effects of motor imagery combined with functional electrical stimulation on upper limb motor function of patients with acute ischemic stroke

    Directory of Open Access Journals (Sweden)

    Shou-feng LIU

    2015-03-01

    Full Text Available Objective To explore the effects of motor imagery (MI combined with the third generation functional electrical stimulation (FES on upper limb motor function in acute ischemic stroke patients with hemiplegia.  Methods Forty acute ischemic stroke patients, within 48 h of onset, were randomly divided into FES group (N = 20 and combination group (FES combined with motor imagery, N = 20. All patients received basic routine rehabilitation training, for example, good limb positioning, accepting braces, balance training and training in the activities of daily living (ADL. FES group received the third generation FES therapy and the combination group also received motor imagery for 2 weeks. All of the patients were assessed with Fugl-Meyer Assessment (FMA, Action Research Arm Test (ARAT and active range of motion (AROM of wrist dorsiflexion before and after 2 weeks of treatment.  Results After 2 weeks of treatment, the 2 groups had significantly higher FMA score, ARAT score and AROM of wrist dorsiflexion than that in pre-treatment (P = 0.000, for all. Besides, the FMA score (t = - 2.528, P = 0.016, ARAT score (t = - 2.562, P = 0.014 and AROM of wrist dorsiflexion (t = - 2.469, P = 0.018 in the combination group were significantly higher than that in the FES group. There were interactions of treatment methods with observation time points (P < 0.05, for all.  Conclusions Motor imagery combined with the third generation FES can effectively promote the recovery of upper limb motor function and motion range of wrist dorsiflexion in patients with acute ischemic stroke. DOI: 10.3969/j.issn.1672-6731.2015.03.008

  9. 5 Hz repetitive transcranial magnetic stimulation over the ipsilesional sensory cortex enhances motor learning after stroke

    Directory of Open Access Journals (Sweden)

    Sonia M Brodie

    2014-03-01

    Full Text Available Sensory feedback is critical for motor learning, and thus to neurorehabilitation after stroke. Whether enhancing sensory feedback by applying excitatory repetitive transcranial magnetic stimulation (rTMS over the ipsilesional primary sensory cortex (IL-S1 might enhance motor learning in chronic stroke has yet to be investigated. The present study investigated the effects of 5 Hz rTMS over IL-S1 paired with skilled motor practice on motor learning, hemiparetic cutaneous somatosensation, and motor function. Individuals with unilateral chronic stroke were pseudo-randomly divided into either Active or Sham 5 Hz rTMS groups (n=11/group. Following stimulation, both groups practiced a Serial Tracking Task (STT with the hemiparetic arm; this was repeated for 5 days. Performance on the STT was quantified by response time, peak velocity, and cumulative distance tracked at baseline, during the 5 days of practice, and at a no-rTMS retention test. Cutaneous somatosensation was measured using two-point discrimination. Standardized sensorimotor tests were performed to assess whether the effects might generalize to impact hemiparetic arm function. The active 5Hz rTMS + training group demonstrated significantly greater improvements in STT performance [response time (F1,286.04=13.016, p< 0.0005, peak velocity (F1,285.95=4.111, p=0.044, and cumulative distance (F1,285.92=4.076, p=0.044] and cutaneous somatosensation (F1,21.15=8.793, p=0.007 across all sessions compared to the sham rTMS + training group. Measures of upper extremity motor function were not significantly different for either group. Our preliminary results suggest that, when paired with motor practice, 5Hz rTMS over IL-S1 enhances motor learning related change in individuals with chronic stroke, potentially as a consequence of improved cutaneous somatosensation, however no improvement in general upper extremity function was observed.

  10. eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

    Science.gov (United States)

    Yasvoina, Marina V.

    Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons

  11. Prediction of functional outcomes in stroke patients: the role of motor patterns according to limb synergies.

    Science.gov (United States)

    Gialanella, Bernardo; Santoro, Raffaele

    2015-10-01

    To address the relationships among motor patterns evaluated according to the limb synergies and functional outcomes in stroke patients and clarify which motor pattern was the most important predictor of functional outcomes. The study was conducted on 208 patients with primary diagnosis of stroke admitted for in-hospital rehabilitation. At entry, the Fugl-Meyer Scale was administered to assess motor function according to limb synergies. Pearson's correlation was used to assess the relationship between variables, and backward stepwise regression analysis was used to identify the outcome determinants. Final functional independence measure (FIM) scores and length of in-hospital stay were the outcome measures. At the end of rehabilitation, motor-FIM scores of patients with extensor and flexor synergies, mixing synergies, and no dependence from the synergies were higher than those of no movements and flexor synergy. Multivariate regression analysis showed that extensor synergy of upper limb was an independent predictor of final motor-FIM, personal care and mobility, extensor synergy of lower limb of locomotion, while mixing synergies of upper limb was an independent predictor of length of in-hospital stay. In stroke rehabilitation, the patients' motor patterns according to the synergies strongly relate with functional outcomes and are important outcome predictors.

  12. Efficacy of motor imagery in post-stroke rehabilitation: a systematic review

    Directory of Open Access Journals (Sweden)

    Puhan Milo A

    2008-03-01

    Full Text Available Abstract Background Evaluation of how Motor Imagery and conventional therapy (physiotherapy or occupational therapy compare to conventional therapy only in their effects on clinically relevant outcomes during rehabilitation of persons with stroke. Design Systematic review of the literature Methods We conducted an electronic database search in seven databases in August 2005 and also hand-searched the bibliographies of studies that we selected for the review. Two reviewers independently screened and selected all randomized controlled trials that compare the effects of conventional therapy plus Motor Imagery to those of only conventional therapy on stroke patients. The outcome measurements were: Fugl-Meyer Stroke Assessment upper extremity score (66 points and Action Research Arm Test upper extremity score (57 points. Due to the high variability in the outcomes, we could not pool the data statistically. Results We identified four randomized controlled trials from Asia and North America. The quality of the included studies was poor to moderate. Two different Motor imagery techniques were used (three studies used audiotapes and one study had occupational therapists apply the intervention. Two studies found significant effects of Motor Imagery in the Fugl-Meyer Stroke Assessment: Differences between groups amounted to 11.0 (1.0 to 21.0 and 3.2 (-4 to 10.3 respectively and in the Action Research Arm Test 6.1 (-6.2 to 18.4 and 15.8 (0.5 to 31.0 respectively. One study did not find a significant effect in the Fugl-Meyer Stroke Assessment and Color trail Test (p = 0.28 but in the task-related outcomes (p > 0.001. Conclusion Current evidence suggests that Motor imagery provides additional benefits to conventional physiotherapy or occupational therapy. However, larger and methodologically sounder studies should be conducted to assess the benefits of Motor imagery.

  13. The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease

    International Nuclear Information System (INIS)

    Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y.

    1990-01-01

    Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine [( 123 I]IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease

  14. Neuronal mechanisms of motor learning are age dependent

    NARCIS (Netherlands)

    Berghuis, Kelly M. M.; De Rond, Veerle; Zijdewind, Inge; Koch, Giacomo; Veldman, Menno P.; Hortobagyi, Tibor

    2016-01-01

    There is controversy whether age-related neuroanatomical and neurophysiological changes in the central nervous system affect healthy old adults' abilities to acquire and retain motor skills. We examined the effects of age on motor skill acquisition and retention and potential underlying mechanisms

  15. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

    Science.gov (United States)

    Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

    2013-01-01

    Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. PMID:23255347

  16. Evidence for cell autonomous AP1 function in regulation of Drosophila motor-neuron plasticity

    Directory of Open Access Journals (Sweden)

    Consoulas Christos

    2003-09-01

    Full Text Available Abstract Background The transcription factor AP1 mediates long-term plasticity in vertebrate and invertebrate central nervous systems. Recent studies of activity-induced synaptic change indicate that AP1 can function upstream of CREB to regulate both CREB-dependent enhancement of synaptic strength as well as CREB-independent increase in bouton number at the Drosophila neuromuscular junction (NMJ. However, it is not clear from this study if AP1 functions autonomously in motor neurons to directly modulate plasticity. Results Here, we show that Fos and Jun, the two components of AP1, are abundantly expressed in motor neurons. We further combine immunohistochemical and electrophysiological analyses with use of a collection of enhancers that tightly restrict AP1 transgene expression within the nervous system to show that AP1 induction or inhibition in, but not outside of, motor neurons is necessary and sufficient for its modulation of NMJ size and strength. Conclusion By arguing against the possibility that AP1 effects at the NMJ occur via a polysynaptic mechanism, these observations support a model in which AP1 directly modulates NMJ plasticity processes through a cell autonomous pathway in the motor neuron. The approach described here may serve as a useful experimental paradigm for analyzing cell autonomy of genes found to influence structure and function of Drosophila motor neurons.

  17. Serotonin Promotes Development and Regeneration of Spinal Motor Neurons in Zebrafish.

    Science.gov (United States)

    Barreiro-Iglesias, Antón; Mysiak, Karolina S; Scott, Angela L; Reimer, Michell M; Yang, Yujie; Becker, Catherina G; Becker, Thomas

    2015-11-03

    In contrast to mammals, zebrafish regenerate spinal motor neurons. During regeneration, developmental signals are re-deployed. Here, we show that, during development, diffuse serotonin promotes spinal motor neuron generation from pMN progenitor cells, leaving interneuron numbers unchanged. Pharmacological manipulations and receptor knockdown indicate that serotonin acts at least in part via 5-HT1A receptors. In adults, serotonin is supplied to the spinal cord mainly (90%) by descending axons from the brain. After a spinal lesion, serotonergic axons degenerate caudal to the lesion but sprout rostral to it. Toxin-mediated ablation of serotonergic axons also rostral to the lesion impaired regeneration of motor neurons only there. Conversely, intraperitoneal serotonin injections doubled numbers of new motor neurons and proliferating pMN-like progenitors caudal to the lesion. Regeneration of spinal-intrinsic serotonergic interneurons was unaltered by these manipulations. Hence, serotonin selectively promotes the development and adult regeneration of motor neurons in zebrafish. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Effects of repetitive transcranial magnetic stimulation on motor recovery and motor cortex excitability in patients with stroke: a randomized controlled trial.

    Science.gov (United States)

    Du, J; Tian, L; Liu, W; Hu, J; Xu, G; Ma, M; Fan, X; Ye, R; Jiang, Y; Yin, Q; Zhu, W; Xiong, Y; Yang, F; Liu, X

    2016-11-01

    Repetitive transcranial magnetic stimulation (rTMS) changes the excitability of the motor cortex and thereby has the potential to enhance motor recovery after stroke. This randomized, sham-controlled, double-blind study was to compare the effects of high-frequency versus low-frequency rTMS on motor recovery during the early phase of stroke and to identify the neurophysiological correlates of motor improvements. A total of 69 first-ever ischemic stroke patients with motor deficits were randomly allocated to receive five daily sessions of 3-Hz ipsilesional rTMS, 1-Hz contralesional rTMS or sham rTMS in addition to standard physical therapy. Outcome measures included motor deficits, neurological scores and cortical excitability, which were assessed at baseline, after the intervention and at 3-month follow-up. The rTMS groups manifested greater motor improvements than the control group, which were sustained for at least 3 months after the end of the treatment sessions. 1-Hz rTMS over the unaffected hemisphere produced more profound effects than 3-Hz rTMS in facilitating upper limb motor performance. There was a significant correlation between motor function improvement and motor cortex excitability change in the affected hemisphere. Repetitive transcranial magnetic stimulation is a beneficial neurorehabilitative strategy for enhancing motor recovery in the acute and subacute phase after stroke. © 2016 EAN.

  19. Highly efficient retrograde gene transfer into motor neurons by a lentiviral vector pseudotyped with fusion glycoprotein.

    Directory of Open Access Journals (Sweden)

    Miyabi Hirano

    Full Text Available The development of gene therapy techniques to introduce transgenes that promote neuronal survival and protection provides effective therapeutic approaches for neurological and neurodegenerative diseases. Intramuscular injection of adenoviral and adeno-associated viral vectors, as well as lentiviral vectors pseudotyped with rabies virus glycoprotein (RV-G, permits gene delivery into motor neurons in animal models for motor neuron diseases. Recently, we developed a vector with highly efficient retrograde gene transfer (HiRet by pseudotyping a human immunodeficiency virus type 1 (HIV-1-based vector with fusion glycoprotein B type (FuG-B or a variant of FuG-B (FuG-B2, in which the cytoplasmic domain of RV-G was replaced by the corresponding part of vesicular stomatitis virus glycoprotein (VSV-G. We have also developed another vector showing neuron-specific retrograde gene transfer (NeuRet with fusion glycoprotein C type, in which the short C-terminal segment of the extracellular domain and transmembrane/cytoplasmic domains of RV-G was substituted with the corresponding regions of VSV-G. These two vectors afford the high efficiency of retrograde gene transfer into different neuronal populations in the brain. Here we investigated the efficiency of the HiRet (with FuG-B2 and NeuRet vectors for retrograde gene transfer into motor neurons in the spinal cord and hindbrain in mice after intramuscular injection and compared it with the efficiency of the RV-G pseudotype of the HIV-1-based vector. The main highlight of our results is that the HiRet vector shows the most efficient retrograde gene transfer into both spinal cord and hindbrain motor neurons, offering its promising use as a gene therapeutic approach for the treatment of motor neuron diseases.

  20. Neonatal exposure to monosodium glutamate results in dysmorphology of orofacial lower motor neurons.

    Science.gov (United States)

    Foran, Lindsey; Kupelian, Chloe; Laroia, Swati; Esper, Jeffrey; Kulesza, Randy Joseph

    2017-06-14

    Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and is stored and released by both neurons and astrocytes. Despite the important role of glutamate as a neurotransmitter, high levels of extracellular glutamate can result in excitotoxicity and apoptosis. Monosodium glutamate (MSG) is a naturally occurring sodium salt of glutamic acid that is used as a flavor enhancer in many processed foods. Neonatal exposure to MSG has been shown to result in neurodegeneration in several forebrain regions, characterized by neuronal loss and neuroendocrine abnormalities. However, the brainstem effects of neonatal monosodium glutamate exposure have not been investigated. It is therefore hypothesized that MSG exposure during the early postnatal period would impact brainstem lower motor neurons involved in feeding behavior. The effect of neonatal MSG exposure on brainstem lower motor neurons was investigated by exposing rat pups to either 4mg/g MSG or saline from postnatal day (P) 4 through 10. On P28, brains were preserved by vascular perfusion with fixative, frozen sectioned and stained for Nïssl substance. The number, size and shape of brainstem motor neurons were compared between MSG and saline-exposed animals. MSG exposure had no impact on the total number of neurons in the nuclei examined. However, MSG exposure was associated with a significant increase in the number of round somata in both the trigeminal and facial nuclei. Furthermore, MSG exposure resulted in significantly smaller neurons in all motor nuclei examined. These results suggest that neonatal exposure to MSG impacts the development of brainstem lower motor neurons which may impact feeding and swallowing behaviors in young animals.

  1. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients.

    Science.gov (United States)

    Boggio, Paulo S; Nunes, Alice; Rigonatti, Sergio P; Nitsche, Michael A; Pascual-Leone, Alvaro; Fregni, Felipe

    2007-01-01

    Recent evidence has suggested that a simple technique of noninvasive brain stimulation - transcranial direct current stimulation (tDCS) - is associated with a significant motor function improvement in stroke patients. We tested the motor performance improvement in stroke patients following 4 weekly sessions of sham, anodal- and cathodal tDCS (experiment 1) and the effects of 5 consecutive daily sessions of cathodal tDCS (experiment 2). A blinded rater evaluated motor function using the Jebsen-Taylor Hand Function Test. There was a significant main effect of stimulation condition (p=0.009) in experiment 1. Furthermore there was a significant motor function improvement after either cathodal tDCS of the unaffected hemisphere (p=0.016) or anodal tDCS of the affected hemisphere (p=0.046) when compared to sham tDCS. There was no cumulative effect associated with weekly sessions of tDCS, however consecutive daily sessions of tDCS (experiment 2) were associated with a significant effect on time (pmotor function improvement in stroke patients; and support that consecutive daily sessions of tDCS might increase its behavioral effects. Because the technique of tDCS is simple, safe and non-expensive; our findings support further research on the use of this technique for the rehabilitation of patients with stroke.

  2. Arm Motor Control as Predictor for Hypertonia After Stroke : A Prospective Cohort Study

    NARCIS (Netherlands)

    de Jong, Lex D.; Hoonhorst, Maurits H.; Stuive, Ilse; Dijkstra, Pieter U.

    de Jong LD, Hoonhorst MH, Stuive 1, Dijkstra PU. Arm motor control as predictor for hypertonia after stroke: a prospective cohort study. Arch Phys Med Rehabil 2011;92:1411-7. Objectives: To analyze the development of hypertonia in the hemiparetic elbow flexors, and to explore the predictive value of

  3. Long-term administration of fluoxetine to improve motor recovery after stroke

    NARCIS (Netherlands)

    Berends, Hanneke I.; IJzerman, Maarten Joost; Movig, Kris L.L.; van Putten, Michel Johannes Antonius Maria

    2011-01-01

    Evaluation of: Chollet F. Tardy J., Albucher J.F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10(2), 123–130 (2011). In this study, the authors examined the effects of administration of fluoxetine for 90 days on the

  4. Rehabilitation after stroke: predictive power of Barthel Index versus a cognitive and a motor index

    DEFF Research Database (Denmark)

    Engberg, A; Bentzen, L; Garde, B

    1995-01-01

    The aim of the present study was to investigate the predictive power of ratings of Barthel Index at Day 40 post stroke, compared with and/or combined with simultaneous ratings from a mobility scale (EG motor index) and a rather simple cognitive test scale (CT50). The parameter to be individually ...

  5. Rehabilitation of stroke patients with apraxia : the role of additional cognitive and motor impairments

    NARCIS (Netherlands)

    van Heugten, C.M.; Dekker, J.; Deelman, B.G.; Stehmann-Saris, J.C; Kinebanian, A

    Purpose : The present study investigated which additional cognitive and motor impairments were present in stroke patients with apraxia and which of these factors influenced the effects of treatment. Method: A group of 33 patients with apraxia were treated according to the guidelines of a therapy

  6. Rehabilitation of stroke patients with apraxia: the role of additional cognitive and motor impairments.

    NARCIS (Netherlands)

    Heugten, C.M. van; Dekker, J.; Deelman, B.G.; Stehmann-Saris, J.C.; Kinebanian, A.

    2000-01-01

    PURPOSE: The present study investigated which additional cognitive and motor impairments were present in stroke patients with apraxia and which of these factors influenced the effects of treatment. METHOD: A group of 33 patients with apraxia were treated according to the guidelines of a therapy

  7. A Role for SMN Exon 7 Splicing in the Selective Vulnerability of Motor Neurons in Spinal Muscular Atrophy

    Science.gov (United States)

    Ruggiu, Matteo; McGovern, Vicki L.; Lotti, Francesco; Saieva, Luciano; Li, Darrick K.; Kariya, Shingo; Monani, Umrao R.; Burghes, Arthur H. M.

    2012-01-01

    Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by homozygous loss of the Survival Motor Neuron 1 (SMN1) gene. In the absence of SMN1, inefficient inclusion of exon 7 in transcripts from the nearly identical SMN2 gene results in ubiquitous SMN decrease but selective motor neuron degeneration. Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do other cells in the spinal cord. This is due to inefficient exon 7 splicing that is intrinsic to motor neurons under normal conditions. We also find that SMN depletion in mammalian cells decreases exon 7 inclusion through a negative feedback loop affecting the splicing of its own mRNA. This mechanism is active in vivo and further decreases the efficiency of exon 7 inclusion specifically in motor neurons of severe-SMA mice. Consistent with expression of lower levels of full-length SMN, we find that SMN-dependent downstream molecular defects are exacerbated in SMA motor neurons. These findings suggest a mechanism to explain the selective vulnerability of motor neurons to loss of SMN1. PMID:22037760

  8. Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-β/BMP signaling and orphan nuclear receptors.

    Directory of Open Access Journals (Sweden)

    Ana Boulanger

    Full Text Available Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment and received by the motor neuron (presynaptic compartment resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation.

  9. Effectiveness of upper limb functional electrical stimulation after stroke for the improvement of activities of daily living and motor function: a systematic review and meta-analysis.

    Science.gov (United States)

    Eraifej, John; Clark, William; France, Benjamin; Desando, Sebastian; Moore, David

    2017-02-28

    Stroke can lead to significant impairment of upper limb function which affects performance of activities of daily living (ADL). Functional electrical stimulation (FES) involves electrical stimulation of motor neurons such that muscle groups contract and create or augment a moment about a joint. Whilst lower limb FES was established in post-stroke rehabilitation, there is a lack of clarity on the effectiveness of upper limb FES. This systematic review aims to evaluate the effectiveness of post-stroke upper limb FES on ADL and motor outcomes. Systematic review of randomised controlled trials from MEDLINE, PsychINFO, EMBASE, CENTRAL, ISRCTN, ICTRP and ClinicalTrials.gov. Citation checking of included studies and systematic reviews. Eligibility criteria: participants > 18 years with haemorrhagic/ischaemic stroke, intervention group received upper limb FES plus standard care, control group received standard care. Outcomes were ADL (primary), functional motor ability (secondary) and other motor outcomes (tertiary). Quality assessment using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Twenty studies were included. No significant benefit of FES was found for objective ADL measures reported in six studies (standardised mean difference (SMD) 0.64; 95% Confidence Interval (CI) [-0.02, 1.30]; total participants in FES group (n) = 67); combination of all ADL measures was not possible. Analysis of three studies where FES was initiated on average within 2 months post-stroke showed a significant benefit of FES on ADL (SMD 1.24; CI [0.46, 2.03]; n = 32). In three studies where FES was initiated more than 1 year after stroke, no significant ADL improvements were seen (SMD -0.10; CI [-0.59, 0.38], n = 35). Quality assessment using GRADE found very low quality evidence in all analyses due to heterogeneity, low participant numbers and lack of blinding. FES is a promising therapy which could play a part in future stroke

  10. Neuropsychology and the relearning of motor skills following stroke

    NARCIS (Netherlands)

    Hochstenbach, J; Mulder, T

    Regaining independent mobility is one of the most important goals in physical therapy with patients suffering from the consequences of stroke. Both physical therapy and occupational therapy are learning processes in which the patient has to remaster old skills or has to learn novel skills. It is

  11. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial.

    Science.gov (United States)

    Chollet, François; Tardy, Jean; Albucher, Jean-François; Thalamas, Claire; Berard, Emilie; Lamy, Catherine; Bejot, Yannick; Deltour, Sandrine; Jaillard, Assia; Niclot, Philippe; Guillon, Benoit; Moulin, Thierry; Marque, Philippe; Pariente, Jérémie; Arnaud, Catherine; Loubinoux, Isabelle

    2011-02-01

    Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial

  12. Targeting the Full Length of the Motor End Plate Regions in the Mouse Forelimb Increases the Uptake of Fluoro-Gold into Corresponding Spinal Cord Motor Neurons

    Directory of Open Access Journals (Sweden)

    Andrew Paul Tosolini

    2013-05-01

    Full Text Available Lower motor neuron dysfunction is one of the most debilitating motor conditions. In this regard, transgenic mouse models of various lower motor neuron dysfunctions provide insight into the mechanisms underlying these pathologies and can also aid the development of new therapies. Viral-mediated gene therapy can take advantage of the muscle-motor neuron topographical relationship to shuttle therapeutic genes into specific populations of motor neurons in these mouse models. In this context, motor end plates (MEPs are highly specialised regions on the skeletal musculature that offer direct access to the pre-synaptic nerve terminals, henceforth to the spinal cord motor neurons. The aim of this study was two-folded. First it was to characterise the exact position of the MEP regions for several muscles of the mouse forelimb using acetylcholinesterase histochemistry. This MEP-muscle map was then used to guide a series of intramuscular injections of Fluoro-Gold (FG in order to characterise the distribution of the innervating motor neurons. This analysis revealed that the MEPs are typically organised in an orthogonal fashion across the muscle fibres and extending throughout the full width of each muscle. Furthermore, targeting the full length of the MEP regions gave rise to a seemingly greater number of labelled motor neurons that are organised into columns spanning through more spinal cord segments than previously reported. The present analysis suggests that targeting the full width of the muscles’ MEP regions with FG increases the somatic availability of the tracer. This process ensures a greater uptake of the tracer by the pre-synaptic nerve terminals, hence maximising the labelling in spinal cord motor neurons. This investigation should have positive implications for future studies involving the somatic delivery of therapeutic genes into motor neurons for the treatment of various motor dysfunctions.

  13. Motor Impairments in Transient Ischemic Attack Increase the Odds of a Subsequent Stroke: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Neha Lodha

    2017-06-01

    Full Text Available Background and purposeTransient ischemic attack (TIA increases the risk for a subsequent stroke. Typical symptoms include motor weakness, gait disturbance, and loss of coordination. The association between the presence of motor impairments during a TIA and the chances of a subsequent stroke has not been examined. In the current meta-analysis, we examine whether the odds of a stroke are greater in TIA individuals who experience motor impairments as compared with those who do not experience motor impairments.MethodsWe conducted a systematic search of electronic databases as well as manual searches of the reference lists of retrieved articles. The meta-analysis included studies that reported an odds ratio relating motor impairments to a subsequent stroke, or the number of individuals with or without motor impairments who experienced a subsequent stroke. We examined these studies using rigorous meta-analysis techniques including random effects model, forest and funnel plots, I2, publication bias, and fail-safe analysis.ResultsTwenty-four studies with 15,129 participants from North America, Australia, Asia, and Europe qualified for inclusion. An odds ratio of 2.11 (95% CI, 1.67–2.65, p = 0.000 suggested that the chances of a subsequent stroke are increased by twofolds in individuals who experience motor impairments during a TIA compared with those individuals who have no motor impairments.ConclusionThe presence of motor impairments during TIA is a significantly high-risk clinical characteristic for a subsequent stroke. The current evidence for motor impairments following TIA relies exclusively on the clinical reports of unilateral motor weakness. A comprehensive examination of motor impairments in TIA will enhance TIA prognosis and restoration of residual motor impairments.

  14. Translocation and neurotoxicity of CdTe quantum dots in RMEs motor neurons in nematode Caenorhabditis elegans

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yunli; Wang, Xiong; Wu, Qiuli; Li, Yiping; Wang, Dayong, E-mail: dayongw@seu.edu.cn

    2015-02-11

    Graphical abstract: - Highlights: • We investigated in vivo neurotoxicity of CdTe QDs on RMEs motor neurons in C. elegans. • CdTe QDs in the range of μg/L caused neurotoxicity on RMEs motor neurons. • Bioavailability of CdTe QDs may be the primary inducer for CdTe QDs neurotoxicity. • Both oxidative stress and cell identity regulate the CdTe QDs neurotoxicity. • CdTe QDs were translocated and deposited into RMEs motor neurons. - Abstract: We employed Caenorhabditis elegans assay system to investigate in vivo neurotoxicity of CdTe quantum dots (QDs) on RMEs motor neurons, which are involved in controlling foraging behavior, and the underlying mechanism of such neurotoxicity. After prolonged exposure to 0.1–1 μg/L of CdTe QDs, abnormal foraging behavior and deficits in development of RMEs motor neurons were observed. The observed neurotoxicity from CdTe QDs on RMEs motor neurons might be not due to released Cd{sup 2+}. Overexpression of genes encoding Mn-SODs or unc-30 gene controlling cell identity of RMEs neurons prevented neurotoxic effects of CdTe QDs on RMEs motor neurons, suggesting the crucial roles of oxidative stress and cell identity in regulating CdTe QDs neurotoxicity. In nematodes, CdTe QDs could be translocated through intestinal barrier and be deposited in RMEs motor neurons. In contrast, CdTe@ZnS QDs could not be translocated into RMEs motor neurons and therefore, could only moderately accumulated in intestinal cells, suggesting that ZnS coating might reduce neurotoxicity of CdTe QDs on RMEs motor neurons. Therefore, the combinational effects of oxidative stress, cell identity, and bioavailability may contribute greatly to the mechanism of CdTe QDs neurotoxicity on RMEs motor neurons. Our results provide insights into understanding the potential risks of CdTe QDs on the development and function of nervous systems in animals.

  15. Chronic Stroke Outcome Measures for Motor Function Intervention Trials: Expert Panel Recommendations.

    Science.gov (United States)

    Bushnell, Cheryl; Bettger, Janet Prvu; Cockroft, Kevin M; Cramer, Steven C; Edelen, Maria Orlando; Hanley, Daniel; Katzan, Irene L; Mattke, Soeren; Nilsen, Dawn M; Piquado, Tepring; Skidmore, Elizabeth R; Wing, Kay; Yenokyan, Gayane

    2015-10-01

    About half of survivors with stroke experience severe and significant long-term disability. The purpose of this article is to review the state of the science and to make recommendations for measuring patient-centric outcomes in interventions for motor improvement in the chronic stroke phase. A 9-member expert panel reviewed evidence to identify measures of upper and lower extremity function used to date as outcomes in trials with patients who experienced a stroke ≥6 months before assessment. Outcome measures were screened using StrokEDGE consensus panel recommendations, and evaluated for availability of a published minimal clinically important difference. Measures meeting these criteria were further evaluated with regard to their level of measurement, psychometric properties, and ability of minimal clinically important difference to capture gains associated with improved function and clinical relevance to patients, to arrive at recommendations. A systematic literature review yielded 115 clinical trials of upper and lower extremity function in chronic stroke that used a total of 34 outcome measures. Seven of these had published minimal clinically important differences and were recommended or highly recommended by StrokEDGE. Those are the Fugl-Meyer Upper Extremity and Lower Extremity scales, Wolf Motor Function Test, Action Research Arm Test, Ten-Meter and Six-Minute Walk Tests, and the Stroke Impact Scale. All had evidence for their psychometric performance, although the strength of evidence for validity varied, especially in populations with chronic stroke Fugl-Meyer Upper and Lower Extremity scales showing the strongest evidence for validity. The panel recommends that the Fugl-Meyer Upper and Lower Extremity scales be used as primary outcomes in intervention trials targeting motor function in populations with chronic stroke. The other 6 measures are recommended as secondary outcomes. © 2015 American Heart Association, Inc.

  16. Enhancement Of Motor Recovery Through Left Dorsolateral Prefrontal Cortex Stimulation After Acute Ischemic Stroke

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    Shahram Oveisgharan

    2017-02-01

    Full Text Available Background: Two previous studies, which investigated transcranial direct current stimulation (tDCS use in motor recovery after acute ischemic stroke, did not show tDCS to be effective in this regard. We speculated that additional left dorsolateral prefrontal cortex ‎(DLPFC ‎stimulation may enhance post stroke motor recovery.  ‎ Methods: In the present randomized clinical trial, 20 acute ischemic stroke patients were recruited. Patients received real motor cortex (M1 stimulation in both arms of the trial. The two arms differed in terms of real vs. sham stimulation over the left DLPFC‎. Motor component of the Fugl-Meyer upper extremity assessment (FM and Action Research Arm Test (ARAT scores were used to assess primary outcomes, and non-linear mixed effects models were used for data analyses. Results: Primary outcome measures improved more and faster among the real stimulation group. During the first days of stimulations, sham group’s FM scores increased 1.2 scores per day, while real group’s scores increased 1.7 scores per day (P = 0.003. In the following days, FM improvement decelerated in both groups. Based on the derived models, a hypothetical stroke patient with baseline FM score of 15 improves to 32 in the sham stimulation group and to 41 in the real stimulation group within the first month after stroke. Models with ARAT scores yielded nearly similar results. Conclusion: The current study results showed that left DLPFC‎ stimulation in conjunction with M1 stimulation resulted in better motor recovery than M1 stimulation alone.

  17. The spasticity in the motor and functional disability in adults with post-stroke hemiparetic

    Directory of Open Access Journals (Sweden)

    Roberta de Oliveira Cacho

    Full Text Available Abstract Introduction: Spasticity acts as a limiting factor in motor and functional recovery after Stroke, impairing the performance of daily living activities. Objective: To analyze the influence of spasticity on main muscle groups and to associate it with motor impairment and functional level of chronic hemiparetic patients after stroke. Methods: Twenty-seven chronic hemiparetic patients of both sexes were selected at the Physical Therapy and Occupational Therapy Service of the Unicamp Clinics Hospital. Assessments were carried out in two sessions, in the first one the motor impairment (Fugl-Meyer Assessment - FM and functional impairment (Barthel Index - BI were evaluated, and in the second, the degree of spasticity of the main muscle groups (Modified Ashworth Scale - MAS. Results: A negative correlation was detected between upper limb spasticity and motor and functional impairment. No muscle group evaluated in the lower limbs showed correlation between muscle tone and the level of impairment of the lower extremity on FM and the functional level measured by BI. Conclusion: Spasticity has been shown to be a negative influence factor in the level of motor and functional impairment of the upper limbs of chronic hemiparetic patients after stroke.

  18. Compromised Motor Dexterity Confounds Processing Speed Task Outcomes in Stroke Patients

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    Essie Low

    2017-09-01

    Full Text Available Most conventional measures of information processing speed require motor responses to facilitate performance. However, although not often addressed clinically, motor impairment, whether due to age or acquired brain injury, would be expected to confound the outcome measure of such tasks. The current study recruited 29 patients (20 stroke and 9 transient ischemic attack with documented reduction in dexterity of the dominant hand, and 29 controls, to investigate the extent to which 3 commonly used processing speed measures with varying motor demands (a Visuo-Motor Reaction Time task, and the Wechsler Adult Intelligence Scale-IV Symbol Search and Coding subtests may be measuring motor-related speed more so than cognitive speed. Analyses include correlations between indices of cognitive and motor speed obtained from two other tasks (Inspection Time and Pegboard task, respectively with the three speed measures, followed by hierarchical regressions to determine the relative contribution of cognitive and motor speed indices toward task performance. Results revealed that speed outcomes on tasks with relatively high motor demands, such as Coding, were largely reflecting motor speed in individuals with reduced dominant hand dexterity. Thus, findings indicate the importance of employing measures with minimal motor requirements, especially when the assessment of speed is aimed at understanding cognitive rather than physical function.

  19. Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Körner, Sonja; Kollewe, Katja; Fahlbusch, Marion; Zapf, Antonia; Dengler, Reinhard; Krampfl, Klaus; Petri, Susanne

    2011-05-01

    The potential linkage between upper (UMN) and lower motor neuron (LMN) involvement in amyotrophic lateral sclerosis (ALS) has not yet been fully elucidated. There is ongoing discussion as to whether ALS is primarily a disease of UMNs or LMNs. We performed a retrospective analysis of 189 ALS patients from our ALS outpatient database to investigate the different spreading patterns of UMN and LMN affection in disease progression in relation to the onset region. The body region with the highest UMN involvement at onset in general also had the highest frequency of LMN signs and vice versa. This is in line with the hypothesis of a focal onset of disease, which then spreads to adjacent areas. However, there was a great variation between ALS phenotypes. These observations support the hypothesis of focal damage of a localized group of motor neurons, which then spreads to adjacent motor neurons. Copyright © 2010 Wiley Periodicals, Inc.

  20. The UNC-4 homeobox protein represses mab-9 expression in DA motor neurons in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Jafari, Gholamali; Appleford, Peter J; Seago, Julian

    2011-01-01

    The T-box transcription factor mab-9 has been shown to be required for the correct fate of the male-specific blast cells B and F, normal posterior hypodermal morphogenesis, and for the correct axon migration of motor neurons that project circumferential commissures to dorsal muscles. In this study......, an RNAi screen designed to identify upstream transcriptional regulators of mab-9 showed that silencing of unc-4 (encoding a paired-class homeodomain protein) increases mab-9::gfp expression in the nervous system, specifically in posterior DA motor neurons. Over-expression of unc-4 from a heat......-shock promoter has the opposite effect, causing repression of mab-9 in various cells. We find that mab-9 expression in unc-37 mutants is also elevated in DA motor neurons, consistent with known roles for UNC-37 as a co-repressor with UNC-4. These results identify mab-9 as a novel target of the UNC-4/UNC-37...

  1. EEG Event-Related Desynchronization of patients with stroke during motor imagery of hand movement

    Science.gov (United States)

    Tabernig, Carolina B.; Carrere, Lucía C.; Lopez, Camila A.; Ballario, Carlos

    2016-04-01

    Brain Computer Interfaces (BCI) can be used for therapeutic purposes to improve voluntary motor control that has been affected post stroke. For this purpose, desynchronization of sensorimotor rhythms of the electroencephalographic signal (EEG) can be used. But it is necessary to study what happens in the affected motor cortex of this people. In this article, we analyse EEG recordings of hemiplegic stroke patients to determine if it is possible to detect desynchronization in the affected motor cortex during the imagination of movements of the affected hand. Six patients were included in the study; four evidenced desynchronization in the affected hemisphere, one of them showed no results and the EEG recordings of the last patient presented high noise level. These results suggest that we could use the desynchronization of sensorimotor rhythms of the EEG signal as a BCI paradigm in a rehabilitation programme.

  2. Neural substrates underlying motor skill learning in chronic hemiparetic stroke patients

    Directory of Open Access Journals (Sweden)

    Stephanie eLefebvre

    2015-06-01

    Full Text Available Motor skill learning is critical in post-stroke motor recovery, but little is known about its underlying neural substrates. Recently, using a new visuomotor skill learning paradigm involving a speed/accuracy trade-off in healthy individuals we identified three subpopulations based on their behavioral trajectories: fitters (in whom improvement in speed or accuracy coincided with deterioration in the other parameter, shifters (in whom speed and/or accuracy improved without degradation of the other parameter, and non-learners. We aimed to identify the neural substrates underlying the first stages of motor skill learning in chronic hemiparetic stroke patients and to determine whether specific neural substrates were recruited in shifters versus fitters. During functional magnetic resonance imaging (fMRI, 23 patients learned the visuomotor skill with their paretic upper limb. In the whole-group analysis, correlation between activation and motor skill learning was restricted to the dorsal prefrontal cortex of the damaged hemisphere (DLPFCdamh: r=-0.82 and the dorsal premotor cortex (PMddamh: r=0.70; the correlations was much lesser (-0.160.25 in the other regions of interest. In a subgroup analysis, significant activation was restricted to bilateral posterior parietal cortices of the fitters and did not correlate with motor skill learning. Conversely, in shifters significant activation occurred in the primary sensorimotor cortexdamh and supplementary motor areadamh and in bilateral PMd where activation changes correlated significantly with motor skill learning (r=0.91. Finally, resting-state activity acquired before learning showed a higher functional connectivity in the salience network of shifters compared with fitters (qFDR<0.05. These data suggest a neuroplastic compensatory reorganization of brain activity underlying the first stages of motor skill learning with the paretic upper limb in chronic hemiparetic stroke patients, with a key role of

  3. Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle

    Science.gov (United States)

    Payne, Anthony M; Zheng, Zhenlin; Messi, María Laura; Milligan, Carol E; González, Estela; Delbono, Osvaldo

    2006-01-01

    IGF-1 is a potent growth factor for both motor neurones and skeletal muscle. Muscle IGF-1 is known to provide target-derived trophic effects on motor neurones. Therefore, IGF-1 overexpression in muscle is effective in delaying or preventing deleterious effects of ageing in both tissues. Since age-related decline in muscle function stems partly from motor neurone loss, a tetanus toxin fragment-C (TTC) fusion protein was created to target IGF-1 to motor neurones. IGF-1–TTC retains IGF-1 activity as indicated by [3H]thymidine incorporation into L6 myoblasts. Spinal cord motor neurones effectively bound and internalized the IGF-1–TTC in vitro. Similarly, IGF-1–TTC injected into skeletal muscles was taken up and retrogradely transported to the spinal cord in vivo, a process prevented by denervation of injected muscles. Three monthly IGF-1–TTC injections into muscles of ageing mice did not increase muscle weight or muscle fibre size, but significantly increased single fibre specific force over aged controls injected with saline, IGF-1, or TTC. None of the injections changed muscle fibre type composition, but neuromuscular junction post-terminals were larger and more complex in muscle fibres injected with IGF-1–TTC, compared to the other groups, suggesting preservation of muscle fibre innervation. This work demonstrates that induced overexpression of IGF-1 in spinal cord motor neurones of ageing mice prevents muscle fibre specific force decline, a hallmark of ageing skeletal muscle. PMID:16293644

  4. ALS-related misfolded protein management in motor neurons and muscle cells.

    Science.gov (United States)

    Galbiati, Mariarita; Crippa, Valeria; Rusmini, Paola; Cristofani, Riccardo; Cicardi, Maria Elena; Giorgetti, Elisa; Onesto, Elisa; Messi, Elio; Poletti, Angelo

    2014-12-01

    Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. An augmented reality system for upper-limb post-stroke motor rehabilitation: a feasibility study.

    Science.gov (United States)

    Assis, Gilda Aparecida de; Corrêa, Ana Grasielle Dionísio; Martins, Maria Bernardete Rodrigues; Pedrozo, Wendel Goes; Lopes, Roseli de Deus

    2016-08-01

    To determine the clinical feasibility of a system based on augmented reality for upper-limb (UL) motor rehabilitation of stroke participants. A physiotherapist instructed the participants to accomplish tasks in augmented reality environment, where they could see themselves and their surroundings, as in a mirror. Two case studies were conducted. Participants were evaluated pre- and post-intervention. The first study evaluated the UL motor function using Fugl-Meyer scale. Data were compared using non-parametric sign tests and effect size. The second study used the gain of motion range of shoulder flexion and abduction assessed by computerized biophotogrammetry. At a significance level of 5%, Fugl-Meyer scores suggested a trend for greater UL motor improvement in the augmented reality group than in the other. Moreover, effect size value 0.86 suggested high practical significance for UL motor rehabilitation using the augmented reality system. System provided promising results for UL motor rehabilitation, since enhancements have been observed in the shoulder range of motion and speed. Implications for Rehabilitation Gain of range of motion of flexion and abduction of the shoulder of post-stroke patients can be achieved through an augmented reality system containing exercises to promote the mental practice. NeuroR system provides a mental practice method combined with visual feedback for motor rehabilitation of chronic stroke patients, giving the illusion of injured upper-limb (UL) movements while the affected UL is resting. Its application is feasible and safe. This system can be used to improve UL rehabilitation, an additional treatment past the traditional period of the stroke patient hospitalization and rehabilitation.

  6. Bobath or motor relearning programme? A follow-up one and four years post stroke.

    Science.gov (United States)

    Langhammer, Birgitta; Stanghelle, Johan K

    2003-11-01

    The purpose of this follow-up one and four years post stroke was to find out whether the initial physiotherapy approach had had any long-term effects on mortality, motor function, postural control, activities of daily living, life quality, follow-up from community services and living conditions. A randomized controlled trial of first time ever stroke patients. Group 1 (n = 33) and group 2 (n = 28) had initial physiotherapy according to the Motor Relearning Programme and Bobath, respectively. The Motor Assessment Scale (MAS), the Sødring Motor Evaluation Scale (SMES), the Barthel ADL Index, the Nottingham Health Profile (NHP) and Berg Balance Scale were used. The following parameters were also registered: incidence of new strokes, other diseases, use of assistive devices, the patient's accommodation and use of services from the community. The mortality rates were similar in the two groups. In both groups the motor function, postural control and ADL had decreased rapidly, leaving many of the patients dependent and with a high risk of falling. Life quality had increased compared to the acute stage, but was still low in comparison with healthy persons. Patients in both groups lived at home, but were dependent on help from relatives and community services. Physiotherapy as follow-up service was seldom used. The initial physiotherapy approach did not seem to have a major influence on the patients' ability to cope in the long-term. This follow-up at one and four years post stroke showed no major influence of two different initial physiotherapy regimens on long-term function. The study confirmed a rapid deterioration of ADL and motor function and an increased dependence on relatives. The study reveals a gap between the intense treatment in the acute phase and little or no follow-up of physiotherapy treatment or other rehabilitation activities later.

  7. Associative Memory Extinction Is Accompanied by Decayed Plasticity at Motor Cortical Neurons and Persistent Plasticity at Sensory Cortical Neurons.

    Science.gov (United States)

    Guo, Rui; Ge, Rongjing; Zhao, Shidi; Liu, Yulong; Zhao, Xin; Huang, Li; Guan, Sodong; Lu, Wei; Cui, Shan; Wang, Shirlene; Wang, Jin-Hui

    2017-01-01

    Associative memory is essential for cognition, in which associative memory cells and their plasticity presumably play important roles. The mechanism underlying associative memory extinction vs. maintenance remains unclear, which we have studied in a mouse model of cross-modal associative learning. Paired whisker and olfaction stimulations lead to a full establishment of odorant-induced whisker motion in training day 10, which almost disappears if paired stimulations are not given in a week, and then recovers after paired stimulation for an additional day. In mice that show associative memory, extinction and recovery, we have analyzed the dynamical plasticity of glutamatergic neurons in layers II-III of the barrel cortex and layers IV-V of the motor cortex. Compared with control mice, the rate of evoked spikes as well as the amplitude and frequency of excitatory postsynaptic currents increase, whereas the amplitude and frequency of inhibitory postsynaptic currents (IPSC) decrease at training day 10 in associative memory mice. Without paired training for a week, these plastic changes are persistent in the barrel cortex and decayed in the motor cortex. If paired training is given for an additional day to revoke associative memory, neuronal plasticity recovers in the motor cortex. Our study indicates persistent neuronal plasticity in the barrel cortex for cross-modal memory maintenance as well as the dynamical change of neuronal plasticity in the motor cortex for memory retrieval and extinction. In other words, the sensory cortices are essential for long-term memory while the behavior-related cortices with the inability of memory retrieval are correlated to memory extinction.

  8. Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice

    KAUST Repository

    Jeong, Suh Young

    2011-10-07

    Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

  9. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    Science.gov (United States)

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. © 2013 Anatomical Society.

  10. Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice.

    Directory of Open Access Journals (Sweden)

    Suh Young Jeong

    Full Text Available Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2, which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

  11. α-Motor neurons are spared from aging while their synaptic inputs degenerate in monkeys and mice.

    Science.gov (United States)

    Maxwell, Nicholas; Castro, Ryan W; Sutherland, Natalia M; Vaughan, Kelli L; Szarowicz, Mark D; de Cabo, Rafael; Mattison, Julie A; Valdez, Gregorio

    2018-02-04

    Motor function deteriorates with advancing age, increasing the risk of adverse health outcomes. While it is well established that skeletal muscles and neuromuscular junctions (NMJs) degenerate with increasing age, the effect of aging on α-motor neurons and their innervating synaptic inputs remains largely unknown. In this study, we examined the soma of α-motor neurons and innervating synaptic inputs in the spinal cord of aged rhesus monkeys and mice, two species with vastly different lifespans. We found that, in both species, α-motor neurons retain their soma size despite an accumulation of large amounts of cellular waste or lipofuscin. Interestingly, the lipofuscin profile varied considerably, indicating that α-motor neurons age at different rates. Although the rate of aging varies, α-motor neurons do not atrophy in old age. In fact, there is no difference in the number of motor axons populating ventral roots in old mice compared to adult mice. Moreover, the transcripts and proteins associated with α-motor neurons do not decrease in the spinal cord of old mice. However, in aged rhesus monkeys and mice, there were fewer cholinergic and glutamatergic synaptic inputs directly abutting α-motor neurons, evidence that aging causes α-motor neurons to shed synaptic inputs. Thus, the loss of synaptic inputs may contribute to age-related dysfunction of α-motor neurons. These findings broaden our understanding of the degeneration of the somatic motor system that precipitates motor dysfunction with advancing age. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  12. Eye-hand coordination and its relationship with sensori-motor impairments in stroke survivors.

    Science.gov (United States)

    Gao, Kelly L; Ng, Shamay S M; Kwok, Joey W Y; Chow, Ray T K; Tsang, William W N

    2010-04-01

    To investigate eye-hand coordination in stroke survivors and its relationship with sensori-motor impairments and hand functioning in daily life. Cross-sectional study. Fifteen subjects with stroke (mean age 62.5 years (standard deviation (SD) 7.1); time post-stroke 5.2 years (SD 3.0)) recruited by convenience sampling. A fast finger-pointing task towards a moving visual target was employed to investigate the differences between the subjects' affected and unaffected hands in terms of reaction time, movement time and accuracy. Their sensori-motor impairments in tactile sensation, handgrip strength, Fugl-Meyer scores and Jebsen Taylor Hand Function Test scores were measured. Significant differences were found between the affected and unaffected hands in terms of movement time and accuracy in finger pointing. Movement time was significantly correlated with tactile sensitivity, handgrip strength and total Fugl-Meyer score, while accuracy correlated with tactile sensitivity and total Fugl-Meyer score. Total scores on the hand function test also correlated significantly with reaction time and movement time. The stroke survivors had poorer eye-hand coordination, in terms of slower movement and reduced accuracy when using their affected hand. These performance measures were significantly correlated with several sensori-motor impairments. A significant correlation was also found between eye-hand coordination performance and hand function test scores.

  13. A Mirror Therapy-Based Action Observation Protocol to Improve Motor Learning After Stroke.

    Science.gov (United States)

    Harmsen, Wouter J; Bussmann, Johannes B J; Selles, Ruud W; Hurkmans, Henri L P; Ribbers, Gerard M

    2015-07-01

    Mirror therapy is a priming technique to improve motor function of the affected arm after stroke. To investigate whether a mirror therapy-based action observation (AO) protocol contributes to motor learning of the affected arm after stroke. A total of 37 participants in the chronic stage after stroke were randomly allocated to the AO or control observation (CO) group. Participants were instructed to perform an upper-arm reaching task as fast and as fluently as possible. All participants trained the upper-arm reaching task with their affected arm alternated with either AO or CO. Participants in the AO group observed mirrored video tapes of reaching movements performed by their unaffected arm, whereas participants in the CO group observed static photographs of landscapes. The experimental condition effect was investigated by evaluating the primary outcome measure: movement time (in seconds) of the reaching movement, measured by accelerometry. Movement time decreased significantly in both groups: 18.3% in the AO and 9.1% in the CO group. Decrease in movement time was significantly more in the AO compared with the CO group (mean difference = 0.14 s; 95% confidence interval = 0.02, 0.26; P = .026). The present study showed that a mirror therapy-based AO protocol contributes to motor learning after stroke. © The Author(s) 2014.

  14. A Neuroprotective Sericin Hydrogel As an Effective Neuronal Cell Carrier for the Repair of Ischemic Stroke.

    Science.gov (United States)

    Wang, Zheng; Wang, Jian; Jin, Yang; Luo, Zhen; Yang, Wen; Xie, Hongjian; Huang, Kai; Wang, Lin

    2015-11-11

    Ischemic stroke causes extensive cellular loss that impairs brain functions, resulting in severe disabilities. No effective treatments are currently available for brain tissue regeneration. The need to develop effective therapeutic approaches for treating stroke is compelling. A tissue engineering approach employing a hydrogel carrying both cells and neurotrophic cytokines to damaged regions is an encouraging alternative for neuronal repair. However, this approach is often challenged by low in vivo cell survival rate, and low encapsulation efficiency and loss of cytokines. To address these limitations, we propose to develop a biomaterial that can form a matrix capable of improving in vivo survival of transplanted cells and reducing in vivo loss of cytokines. Here, we report that using sericin, a natural protein from silk, we have fabricated a genipin-cross-linked sericin hydrogel (GSH) with porous structure and mild swelling ratio. The GSH supports the effective attachment and growth of neurons in vitro. Strikingly, our data reveal that sericin protein is intrinsically neurotrophic and neuroprotective, promoting axon extension and branching as well as preventing primary neurons from hypoxia-induced cell death. Notably, these functions are inherited by the GSH's degradation products, which might spare a need of incorporating costly cytokines. We further demonstrate that this neurotrophic effect is dependent on the Lkb1-Nuak1 pathway, while the neuroprotective effect is realized through regulating the Bcl-2/Bax protein ratio. Importantly, when transplanted in vivo, the GSH gives a high cell survival rate and allows the cells to continuously proliferate. Together, this work unmasks the neurotrophic and neuroprotective functions for sericin and provides strong evidence justifying the GSH's suitability as a potential neuronal cell delivery vehicle for ischemic stroke repair.

  15. Motor rehabilitation after traumatic brain injury and stroke - Advances in assessment and therapy.

    Science.gov (United States)

    Platz, Thomas; Hesse, S.; Mauritz, K.-H.

    1999-01-01

    A long-term goal in motor rehabilitation is that treatment is not selected on the basis of 'schools of thought', but rather, based on knowledge about efficacy and effectiveness of specific interventions for specific situations (e.g. functional syndromes). Motor dysfunction after stroke or TBI can be caused by many different functional syndromes such as paresis, ataxia, deafferentaion, visuo-perceptual deficits, or apraxia. Examples are provided showing that theory-based analysis of motor behavior makes it possible to describe 'syndrome-specific motor deficits'. Its potential implications for motor rehabilitation are that our understanding of altered motor behavior as well as specific therapeutic approaches might be promoted. A methodological prerequisite for clinical trials in rehabilitation is knowledge about test properties of assessment tools in follow-up situations such as test-retest reliability and responsiveness to change. Test-retest reliability assesses whether a test can produce stable measures with test repetition, while sensitivity to change reflects whether a test detects changes that occur over time. Exemplifying these considerations, a reliability and validity study of a kinematic arm movement analysis is summarized. In terms of new therapeutic developments, two examples of clinical therapeutic studies are provided assessing the efficacy of specific inter-ventions for specific situations in arm and gait rehabilitation: the Arm Ability Training for high functioning hemiparetic stroke and TBI patients, and the treadmill training for non-ambulatory hemiparetic patients. In addition, a new technical development, a machine-controlled gait trainer ist introduced.

  16. Increased reward in ankle robotics training enhances motor control and cortical efficiency in stroke.

    Science.gov (United States)

    Goodman, Ronald N; Rietschel, Jeremy C; Roy, Anindo; Jung, Brian C; Diaz, Jason; Macko, Richard F; Forrester, Larry W

    2014-01-01

    Robotics is rapidly emerging as a viable approach to enhance motor recovery after disabling stroke. Current principles of cognitive motor learning recognize a positive relationship between reward and motor learning. Yet no prior studies have established explicitly whether reward improves the rate or efficacy of robotics-assisted rehabilitation or produces neurophysiologic adaptations associated with motor learning. We conducted a 3 wk, 9-session clinical pilot with 10 people with chronic hemiparetic stroke, randomly assigned to train with an impedance-controlled ankle robot (anklebot) under either high reward (HR) or low reward conditions. The 1 h training sessions entailed playing a seated video game by moving the paretic ankle to hit moving onscreen targets with the anklebot only providing assistance as needed. Assessments included paretic ankle motor control, learning curves, electroencephalograpy (EEG) coherence and spectral power during unassisted trials, and gait function. While both groups exhibited changes in EEG, the HR group had faster learning curves (p = 0.05), smoother movements (p motor learning for restoring mobility.

  17. The efficacy of mirror therapy combined with conventional stroke rehabilitation program on motor and functional recovery

    Directory of Open Access Journals (Sweden)

    Selen Kuzgun

    2012-12-01

    Full Text Available OBJECTIVE: A variety of methods is used in the treatment of upper extremity functional impairment after stroke.In recent years, a new therapeutic approach in the treatment of stroke rehabilitation is the mirror therapy.The purpose of this study is to investigate the efficacy of mirror therapy,which is applied through motor imagination training, combined with conventional stroke rehabilitation program on upper extremity motor and functional recovery in patients with subacute stroke. MATERIAL and METHODS: This is a randomized,prospective,controlled single-blind trial.The study included 20 patients who were diagnosed with stroke.Patients were randomly divided into two groups:first group received conventional rehabilitation program and the second group received conventional rehabilitation program plus mirror therapy on nonparetic upper extremity consisting of wrist extension daily 4 times for 15minutes per session. Both groups received the conventional rehabilitation program for 4 weeks, 5 days a week and daily 1-2h. All patients were evaluated at baseline and at the end of the treatment(week 4.The evaluations were performed by using Brunnstrom Staging, Fugl Meyer Motor Function Scale(FM,Barthel Index(BI and goniometric measurement of wrist extension. RESULTS: The Brunnstrom stage(p<0.01, total score on FM and BI scores (p<0.01 were improved at week 4 compared to the baseline, whereas wrist subscore on FM and the goniometric measurements of the wrist and wrist extension were significantly improved only in group II.The two treatment groups were not statistically different in terms of posttreatment evaluation parameters. CONCLUSION: In our study,the mirror therapy combined with conventional rehabilitation program was not superior to conventional rehabilitation program alone in terms of upper extremity motor and functional recovery.

  18. Enhanced motor function and its neurophysiological correlates after navigated low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in stroke.

    Science.gov (United States)

    Bashir, Shahid; Vernet, Marine; Najib, Umer; Perez, Jennifer; Alonso-Alonso, Miguel; Knobel, Mark; Yoo, Woo-Kyoung; Edwards, Dylan; Pascual-Leone, Alvaro

    2016-08-11

    The net effect of altered interhemispheric interactions between homologous motor cortical areas after unilateral stroke has been previously reported to contribute to residual hemiparesis. Using this framework, we hypothesized that navigated 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the contralesional hemisphere would induce a stronger physiological and behavioural response in patients with residual motor deficit than in healthy subjects, because an imbalance in interhemispheric excitability may underlie motor dysfunction. Navigated rTMS was conducted in 8 chronic stroke patients (67.50±13.77 years) and in 8 comparable normal subjects (57.38±9.61 years). We evaluated motor function (Finger tapping, Nine Hole Peg test, Strength Index and Reaction Time) as well as the excitatory and inhibitory function (resting motor threshold, motor evoked potential amplitude, intra-cortical inhibition and facilitation, and silent period) of the stimulated and non-stimulated motor cortex before and after navigated rTMS. rTMS induced an increase in excitability in the ipsilesional (non-stimulated) motor cortex and led to improved performance in the finger tapping task and pinch force task. These physiological and behavioral effects were more prominent (or robust) in the group of stroke patients than in the control group. Navigated low-frequency rTMS involving precise and consistent targeting of the contralesional hemisphere in stroke patients enhanced the cortical excitability of the ipsilesional hemisphere and the motor response of the hemiparetic hand.

  19. Modeling motor neuron disease : the matter of time

    NARCIS (Netherlands)

    Arbab, Mandana; Baars, Susanne; Geijsen, Niels

    2014-01-01

    Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived

  20. Neuronal nicotinic receptor agonists ameliorate spontaneous motor asymmetries and motor discoordination in a unilateral mouse model of Parkinson's disease.

    Science.gov (United States)

    Kucinski, Aaron; Wersinger, Scott; Stachowiak, Ewa K; Corso, Thomas D; Parry, Matthew J; Zhang, Jenny; Jordan, Kristen; Letchworth, Sharon; Bencherif, Merouane; Stachowiak, Michal K

    2013-10-01

    The degeneration of the nigrostriatal dopamine (DA) system underlies the motor deficits in Parkinson's disease (PD). In recent years, epidemiological reports that smokers have lower incidences of PD have brought attention to the nicotinic acetylcholine system as a potential target for novel therapeutics. Nicotine, an agonist of neuronal nicotinic receptors (NNRs), modulates functions relevant to PD via stimulation of dopaminergic transmission in the nigrostriatal pathway, particularly via activation of α6β2* and α4β2* NNRs. Recently, reduced support of DA neurons by neurotrophic growth factors has been described in PD. Fibroblast growth factor (FGF) is critical for the development and protection of adult DA neurons. In FGF-2 knockout mice and the related th-fgfr1(tk-) mouse model there is heightened sensitivity to DA neuronal oxidative neurotoxin 6-hydroxydopamine (6-OHDA). In the present study, FGF-deficient transgenic mice th-fgfr1(tk-) were used to analyze the effects of novel full (TC-8831) and partial (TC-8581) agonists of β2-containing nicotinic receptors on impaired motor behavior following unilateral 6-OHDA lesions. The lesions generated spontaneous (drug-naïve) turning asymmetries that correlated exponentially with the depletion of DA biomarkers in the lesioned striata. These mice also exhibited a reduced capacity to remain on the accelerating rotarod. Oral administration of TC-8831, an NNR agonist with high specificity for β2 subunits and a full agonist at producing DA release from striatal synaptosomes, attenuated unidirectional turning and improved motor coordination. In contrast, partial β2 NNR agonist TC-8581 had no effect on behaviors in this model. This study demonstrates the potential of NNR targeting-compounds to facilitate motor function in PD. © 2013. Published by Elsevier Inc. All rights reserved.

  1. Rehabilitation after stroke: predictive power of Barthel Index versus a cognitive and a motor index

    DEFF Research Database (Denmark)

    Engberg, A; Bentzen, L; Garde, B

    1995-01-01

    The aim of the present study was to investigate the predictive power of ratings of Barthel Index at Day 40 post stroke, compared with and/or combined with simultaneous ratings from a mobility scale (EG motor index) and a rather simple cognitive test scale (CT50). The parameter to be individually...... predicted was the need for special living facilities and support at discharge from a rehabilitation hospital, as well as six months later; 53 stroke patients with age median 68 years were included in this prospective study. It was shown that a combination of Barthel Index and CT50 had a stronger predictive...

  2. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    Science.gov (United States)

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  3. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Radunovic, Aleksandar; Annane, Djillali; Rafiq, Muhammad K; Brassington, Ruth; Mustfa, Naveed

    2017-10-06

    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009. To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention. We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies. Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care. For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies. For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of

  4. Local-circuit phenotypes of layer 5 neurons in motor-frontal cortex of YFP-H mice

    Directory of Open Access Journals (Sweden)

    Jianing Yu

    2008-12-01

    Full Text Available Layer 5 pyramidal neurons comprise an important but heterogeneous group of cortical projection neurons. In motor-frontal cortex, these neurons are centrally involved in the cortical control of movement. Recent studies indicate that local excitatory networks in mouse motor-frontal cortex are dominated by descending pathways from layer 2/3 to 5. However, those pathways were identified in experiments involving unlabeled neurons in wild type mice. Here, to explore the possibility of class-specific connectivity in this descending pathway, we mapped the local sources of excitatory synaptic input to a genetically labeled population of cortical neurons: YFP-positive layer 5 neurons of YFP-H mice. We found, first, that in motor cortex, YFP-positive neurons were distributed in a double blade, consistent with the idea of layer 5B having greater thickness in frontal neocortex. Second, whereas unlabeled neurons in upper layer 5 received their strongest inputs from layer 2, YFP-positive neurons in the upper blade received prominent layer 3 inputs. Third, YFP-positive neurons exhibited distinct electrophysiological properties, including low spike frequency adaptation, as reported previously. Our results with this genetically labeled neuronal population indicate the presence of distinct local-circuit phenotypes among layer 5 pyramidal neurons in mouse motor-frontal cortex, and present a paradigm for investigating local circuit organization in other genetically labeled populations of cortical neurons.

  5. Late onset GM2 gangliosidosis presenting with motor neuron disease: an autopsy case.

    Science.gov (United States)

    Yokoyama, Teruo; Nakamura, Seigo; Horiuchi, Emiko; Ishiyama, Miyako; Kawashima, Rei; Nakamura, Kazuo; Hasegawa, Kazuko; Yagishita, Saburo

    2014-06-01

    Adult-onset GM2 gangliosidosis is very rare and only three autopsy cases have been reported up to now. We report herein an autopsy case of adult-onset GM2 gangliosidosis. The patient developed slowly progressive motor neuron disease-like symptoms after longstanding mood disorder and cognitive dysfunction. He developed gait disturbance and weakness of lower limbs at age 52 years. Because of progressive muscle weakness and atrophy, he became bed-ridden at age 65. At age of 68, he died. His neurological findings presented slight cognitive disturbance, slight manic state, severe muscle weakness, atrophy of four limbs and no extrapyramidal signs and symptoms, and cerebellar ataxia. Neuropathologically, mild neuronal loss and abundant lipid deposits were noted in the neuronal cytoplasm throughout the nervous system, including peripheral autonomic neurons. The most outstanding findings were marked neuronal loss and distended neurons in the anterior horn of the spinal cord, which supports his clinical symptomatology of lower motor neuron disease in this case. The presence of lipofuscin, zebra bodies and membranous cytoplasmic bodies (MCB) and the increase of GM2 ganglioside by biochemistry led to diagnosis of GM2 gangliosidosis. © 2013 Japanese Society of Neuropathology.

  6. Maximization of learning speed in the motor cortex due to neuronal redundancy.

    Directory of Open Access Journals (Sweden)

    Ken Takiyama

    2012-01-01

    Full Text Available Many redundancies play functional roles in motor control and motor learning. For example, kinematic and muscle redundancies contribute to stabilizing posture and impedance control, respectively. Another redundancy is the number of neurons themselves; there are overwhelmingly more neurons than muscles, and many combinations of neural activation can generate identical muscle activity. The functional roles of this neuronal redundancy remains unknown. Analysis of a redundant neural network model makes it possible to investigate these functional roles while varying the number of model neurons and holding constant the number of output units. Our analysis reveals that learning speed reaches its maximum value if and only if the model includes sufficient neuronal redundancy. This analytical result does not depend on whether the distribution of the preferred direction is uniform or a skewed bimodal, both of which have been reported in neurophysiological studies. Neuronal redundancy maximizes learning speed, even if the neural network model includes recurrent connections, a nonlinear activation function, or nonlinear muscle units. Furthermore, our results do not rely on the shape of the generalization function. The results of this study suggest that one of the functional roles of neuronal redundancy is to maximize learning speed.

  7. Functional and motor outcome 5 years after stroke is equivalent to outcome at 2 months: follow-up of the collaborative evaluation of rehabilitation in stroke across Europe.

    Science.gov (United States)

    Meyer, Sarah; Verheyden, Geert; Brinkmann, Nadine; Dejaeger, Eddy; De Weerdt, Willy; Feys, Hilde; Gantenbein, Andreas R; Jenni, Walter; Laenen, Annouschka; Lincoln, Nadina; Putman, Koen; Schuback, Birgit; Schupp, Wilfried; Thijs, Vincent; De Wit, Liesbet

    2015-06-01

    Recovery of patients within the first 6 months after stroke is well documented, but there has been little research on long-term recovery. The aim of this study was to analyze functional and motor recovery between admission to rehabilitation centres and 5 years after stroke. This follow-up of the Collaborative Evaluation of Rehabilitation in Stroke Across Europe study, included patients from 4 European rehabilitation centres. Patients were assessed on admission, at 2 and 6 months, and 5 years after stroke, using the Barthel Index, Rivermead Motor Assessment Gross Function, Leg and Trunk function, and Arm function. Linear mixed models were used, corrected for baseline characteristics. To account for the drop-out during follow-up, the analysis is likelihood-based (assumption of missingness at random). A total of 532 patients were included in this study, of which 238 were followed up at 5 years post stroke. Mean age at stroke onset was 69 (±10 SD) years, 53% were men, 84% had ischemic strokes, and 53% had left-sided motor impairment. Linear mixed model analysis revealed a significant deterioration for all 4 outcomes between 6 months and 5 years (Pstroke. Higher age (Pstroke severity on admission (Pstroke severity negatively affected recovery up to 5 years after stroke. © 2015 American Heart Association, Inc.

  8. Unique nuclear vacuoles in the motor neurons of conditional ADAR2-knockout mice.

    Science.gov (United States)

    Sasaki, Shoichi; Takenari Yamashita; Hideyama, Takuto; Kwak, Shin

    2014-03-06

    A reduction in adenosine deaminase acting on RNA 2 (ADAR2) activity causes the death of spinal motor neurons specifically via the GluA2 Q/R site-RNA editing failure in sporadic amyotrophic lateral sclerosis (ALS). We studied, over time, the spinal cords of ADAR2-knockout mice, which are the mechanistic model mice for sporadic ALS, using homozygous ADAR2(flox/flox)/VAChT-Cre.Fast (AR2), homozygous ADAR2(flox/flox)/VAChT-Cre.Slow (AR2Slow), and heterozygous ADAR2(flox/+)/VAChT-Cre.Fast (AR2H) mice. The conditional ADAR2-knockout mice were divided into 3 groups by stage: presymptomatic (AR2H mice), early symptomatic (AR2 mice, AR2H mice) and late symptomatic (AR2Slow mice). Light-microscopically, some motor neurons in AR2 and AR2H mice (presymptomatic) showed simple neuronal atrophy and astrogliosis, and AR2H (early symptomatic) and AR2Slow mice often showed vacuoles predominantly in motor neurons. The number of vacuole-bearing anterior horn neurons decreased with the loss of anterior horn neurons in AR2H mice after 40 weeks of age. Electron-microscopically, in AR2 mice, while the cytoplasm of normal-looking motor neurons was almost always normal-appearing, the interior of dendrites was frequently loose and disorganized. In AR2H and AR2Slow mice, large vacuoles without a limiting membrane were observed in the anterior horns, preferentially in the nuclei of motor neurons, astrocytes and oligodendrocytes. Nuclear vacuoles were not observed in AR2res (ADAR2(flox/flox)/VAChT-Cre.Fast/GluR-B(R/R)) mice, in which motor neurons express edited GluA2 in the absence of ADAR2. These findings suggest that ADAR2-reduction is associated with progressive deterioration of nuclear architecture, resulting in vacuolated nuclei due to a Ca(2+)-permeable AMPA receptor-mediated mechanism. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. The kinesin light chain gene: its mapping and exclusion in mouse and human forms of inherited motor neuron degeneration

    NARCIS (Netherlands)

    Hafezparast, M.; Witherden, A.; Nicholson, S.; Bermingham, N.; Mackin, J.; ten Asbroek, A.; Ball, S.; Peters, J.; Baas, F.; Martin, J. E.; Fisher, E. M.

    1999-01-01

    The underlying genetic cause is known for only 10-20% of familial motor neuron disease (MND). Thus the genes involved in the aetiology of 80-90% of familial MND remain to be determined, and animal models are powerful tools for undertaking this task. We have mapped a heritable form of motor neuron

  10. HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.

    Science.gov (United States)

    Heilman, Patrick L; Song, SungWon; Miranda, Carlos J; Meyer, Kathrin; Srivastava, Amit K; Knapp, Amy; Wier, Christopher G; Kaspar, Brian K; Kolb, Stephen J

    2017-11-01

    Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Advance care planning in motor neuron disease: A qualitative study of caregiver perspectives.

    Science.gov (United States)

    Murray, Leigh; Butow, Phyllis N; White, Kate; Kiernan, Matthew C; D'Abrew, Natalie; Herz, Helen

    2016-05-01

    Motor neuron disease is a fatal disease, characterised by progressive loss of motor function, often associated with cognitive deterioration and, in some, the development of frontotemporal dementia. Life-sustaining technologies are available (e.g. non-invasive ventilation and enteral nutrition) but may compromise quality of life for some patients. Timely commencement of 'Advance Care Planning' enables patients to participate in future care choices; however, this approach has rarely been explored in motor neuron disease. We aimed to investigate caregiver perspectives on the acceptability and impact of advance care planning, documented in a letter format, for patients with motor neuron disease and caregivers. This is a qualitative cross-sectional study. Data were analysed by a narrative synthesis approach. Structured interviews were held with 18 former caregivers of deceased patients with motor neuron disease. A total of 10 patients had created a disease-specific advanced directive, 'Letter of Future Care', and 8 had not. A total of four global themes emerged: Readiness for death, Empowerment, Connections and Clarifying decisions and choices. Many felt the letter of future care was or would be beneficial, engendering autonomy and respect for patients, easing difficult decision-making and enhancing communication within families. However, individuals' 'readiness' to accept encroaching death would influence uptake. Appropriate timing to commence advance care planning may depend on case-based clinical and personal characteristics. Advance care planning can assist patients to achieve a sense of control and 'peace of mind' and facilitates important family discussion. However, the timing and style of its introduction needs to be approached sensitively. Tools and strategies for increasing the efficacy of advance care planning for motor neuron disease should be evaluated and implemented. © The Author(s) 2016.

  12. Prostaglandin E2 facilitates neurite outgrowth in a motor neuron-like cell line, NSC-34

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    Hiroshi Nango

    2017-10-01

    Full Text Available Prostaglandin E2 (PGE2 exerts various biological effects by binding to E-prostanoid receptors (EP1-4. Although recent studies have shown that PGE2 induces cell differentiation in some neuronal cells such as mouse DRG neurons and sensory neuron-like ND7/23 cells, it is unclear whether PGE2 plays a role in differentiation of motor neurons. In the present study, we investigated the mechanism of PGE2-induced differentiation of motor neurons using NSC-34, a mouse motor neuron-like cell line. Exposure of undifferentiated NSC-34 cells to PGE2 and butaprost, an EP2-selective agonist, resulted in a reduction of MTT reduction activity without increase the number of propidium iodide-positive cells and in an increase in the number of neurite-bearing cells. Sulprostone, an EP1/3 agonist, also significantly lowered MTT reduction activity by 20%; however, no increase in the number of neurite-bearing cells was observed within the concentration range tested. PGE2-induced neurite outgrowth was attenuated significantly in the presence of PF-0441848, an EP2-selective antagonist. Treatment of these cells with dibutyryl-cAMP increased the number of neurite-bearing cells with no effect on cell proliferation. These results suggest that PGE2 promotes neurite outgrowth and suppresses cell proliferation by activating the EP2 subtype, and that the cAMP-signaling pathway is involved in PGE2-induced differentiation of NSC-34 cells. Keywords: Prostaglandin E2, E-prostanoid receptors, Motor neuron, Neurite outgrowth, cAMP

  13. Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Li; Wu, Zhou; Baba, Masashi [Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582 (Japan); Peters, Christoph [Institute fuer Molekulare Medizin und Zellforshung, Albert-Ludwings-Universitaet Freiburg, D-79104 Freiburg (Germany); Uchiyama, Yasuo [Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo (Japan); Nakanishi, Hiroshi, E-mail: nakan@dent.kyushu-u.ac.jp [Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582 (Japan)

    2010-08-27

    Research highlights: {yields} Cathepsin B (CB), a lysosomal cysteine protease, is expressed in neuron and glia. {yields} CB increased in hypogrossal nucleus neurons after nerve injury in adult mice. {yields} CB-deficiency significantly increased the mean survival ratio of injured neurons. {yields} Thus, CB plays a critical role in axotomy-induced neuronal death in adult mice. -- Abstract: There are significant differences in the rate of neuronal death after peripheral nerve injury between species. The rate of neuronal death of motor neurons after nerve injury in the adult rats is very low, whereas that in adult mice is relatively high. However, the understanding of the mechanism underlying axotomy-induced motor neuron death in adult mice is limited. Cathepsin B (CB), a typical cysteine lysosomal protease, has been implicated in three major morphologically distinct pathways of cell death; apoptosis, necrosis and autophagic cell death. The possible involvement of CB in the neuronal death of hypogrossal nucleus (HGN) neurons after nerve injury in adult mice was thus examined. Quantitative analyses showed the mean survival ratio of HGN neurons in CB-deficient (CB-/-) adult mice after nerve injury was significantly greater than that in the wild-type mice. At the same time, proliferation of microglia in the injured side of the HGN of CB-/- adult mice was markedly reduced compared with that in the wild-type mice. On the injured side of the HGN in the wild-type adult mice, both pro- and mature forms of CB markedly increased in accordance with the increase in the membrane-bound form of LC3 (LC3-II), a marker protein of autophagy. Furthermore, the increase in CB preceded an increase in the expression of Noxa, a major executor for axotomy-induced motor neuron death in the adult mouse. Conversely, expression of neither Noxa or LC3-II was observed in the HGN of adult CB-/- mice after nerve injury. These observations strongly suggest that CB plays a critical role in axotomy

  14. Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease.

    Science.gov (United States)

    Winner, Beate; Marchetto, Maria C; Winkler, Jürgen; Gage, Fred H

    2014-09-15

    While motor neuron diseases are currently incurable, induced pluripotent stem cell research has uncovered some disease-relevant phenotypes. We will discuss strategies to model different aspects of motor neuron disease and the specific neurons involved in the disease. We will then describe recent progress to investigate common forms of motor neuron disease: amyotrophic lateral sclerosis, hereditary spastic paraplegia and spinal muscular atrophy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. TRANSGENIC GDNF POSITIVELY INFLUENCES PROLIFERATION, DIFFERENTIATION, MATURATION AND SURVIVAL OF MOTOR NEURONS PRODUCED FROM MOUSE EMBRYONIC STEM CELLS.

    Directory of Open Access Journals (Sweden)

    Daniel Édgar Cortés

    2016-09-01

    Full Text Available Embryonic stem cells (ESC are pluripotent and thus can differentiate into every cell type present in the body. Directed differentiation into motor neurons has been described for pluripotent cells. Although neurotrophic factors promote neuronal survival, their role in neuronal commitment is elusive. Here, we developed double-transgenic lines of mouse ESC that constitutively produce Glial cell-derived neurotrophic factor (GDNF and also contain a GFP reporter, driven by HB9, which is expressed only by postmitotic motor neurons. After lentiviral transduction, ESC lines integrated and expressed the human GDNF gene without altering pluripotency markers before differentiation. Further, GDNF-ESC showed significantly higher spontaneous release of this neurotrophin to the medium, when compared to controls. To study motor neuron induction, control and GDNF cell lines were grown as embryoid bodies and stimulated with retinoic acid and Sonic Hedgehog. In GDNF-overexpressing cells, a significant increase of proliferative Olig2+ precursors, which are specified as spinal motor neurons, was found. Accordingly, GDNF increases the yield of cells with the pan motor neuronal markers HB9, monitored by GFP expression, and Isl1. At terminal differentiation, almost all differentiated neurons express phenotypic markers of motor neurons in GDNF cultures, with lower proportions in control cells. To test if the effects of GDNF were present at early differentiation stages, exogenous recombinant human GDNF was added to control ESC, also resulting in enhanced motor neuron differentiation. This effect was abolished by the co-addition of neutralizing anti-GDNF antibodies, strongly suggesting that differentiating ESC are responsive to GDNF. Using the HB9::GFP reporter, motor neurons were selected for electrophysiological recordings. Motor neurons differentiated from GDNF-ESC, compared to control motor neurons, showed greater electrophysiological maturation, characterized by

  16. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

    NARCIS (Netherlands)

    Simpson, Claire L.; Lemmens, Robin; Miskiewicz, Katarzyna; Broom, Wendy J.; Hansen, Valerie K.; van Vught, Paul W. J.; Landers, John E.; Sapp, Peter; Van Den Bosch, Ludo; Knight, Joanne; Neale, Benjamin M.; Turner, Martin R.; Veldink, Jan H.; Ophoff, Roel A.; Tripathi, Vineeta B.; Beleza, Ana; Shah, Meera N.; Proitsi, Petroula; Van Hoecke, Annelies; Carmeliet, Peter; Horvitz, H. Robert; Leigh, P. Nigel; Shaw, Christopher E.; van den Berg, Leonard H.; Sham, Pak C.; Powell, John F.; Verstreken, Patrik; Brown, Robert H.; Robberecht, Wim; Al-Chalabi, Ammar

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both

  17. Inflammatory cells in the peripheral nervous system in motor neuron disease

    NARCIS (Netherlands)

    Kerkhoff, H.; Troost, D.; Louwerse, E. S.; van Dijk, M.; Veldman, H.; Jennekens, F. G.

    1993-01-01

    We examined post-mortem material of the peripheral nervous system of 26 cases of motor neuron disease (MND) for the presence of lymphocyte subsets and macrophages. Findings were quantified and compared with those in control nerves. Lymphocytes in chronic and acute axonal degeneration were studied in

  18. Progressive Apraxia of Speech as a Sign of Motor Neuron Disease

    Science.gov (United States)

    Duffy, Joseph R.; Peach, Richard K.; Strand, Edythe A.

    2007-01-01

    Purpose: To document and describe in detail the occurrence of apraxia of speech (AOS) in a group of individuals with a diagnosis of motor neuron disease (MND). Method: Seven individuals with MND and AOS were identified from among 80 patients with a variety of neurodegenerative diseases and AOS (J. R. Duffy, 2006). The history, presenting…

  19. The Effects of Two Different Stretching Programs on Balance Control and Motor Neuron Excitability

    Science.gov (United States)

    Kaya, Fatih; Biçer, Bilal; Yüktasir, Bekir; Willems, Mark E. T.; Yildiz, Nebil

    2018-01-01

    We examined the effects of training (4d/wk for 6 wks) with static stretching (SS) or contract-relax proprioceptive neuromuscular facilitation (PNF) on static balance time and motor neuron excitability. Static balance time, H[subscript max]/M[subscript max] ratios and H-reflex recovery curves (HRRC) were measured in 28 healthy subjects (SS: n = 10,…

  20. Single photon emission computed tomography in motor neuron disease with dementia

    Energy Technology Data Exchange (ETDEWEB)

    Sawada, H.; Udaka, F.; Kishi, Y.; Seriu, N.; Ohtani, S.; Abe, K.; Mezaki, T.; Kameyama, M.; Honda, M.; Tomonobu, M.

    1988-12-01

    Single photon emission computed tomography with (123 I) isopropylamphetamine was carried out on a patient with motor neutron disease with dementia. (123 I) uptake was decreased in the frontal lobes. This would reflect the histopathological findings such as neuronal loss and gliosis in the frontal lobes.

  1. In vitro generation of motor neuron precursors from mouse embryonic stem cells using mesoporous nanoparticles

    DEFF Research Database (Denmark)

    Garcia-Bennett, Alfonso E; König, Niclas; Abrahamsson, Ninnie

    2014-01-01

    Aim: Stem cell-derived motor neurons (MNs) are utilized to develop replacement strategies for spinal cord disorders. Differentiation of embryonic stem cells into MN precursors involves factors and their repeated administration. We investigated if delivery of factors loaded into mesoporous nanopar...

  2. Endothelin-1 is over-expressed in amyotrophic lateral sclerosis and induces motor neuron cell death

    NARCIS (Netherlands)

    Ranno, Eugenia; D'Antoni, Simona; Spatuzza, Michela; Berretta, Antonio; Laureanti, Floriana; Bonaccorso, Carmela M.; Pellitteri, Rosalia; Longone, Patrizia; Spalloni, Alida; Iyer, Anand M.; Aronica, Eleonora; Catania, Maria Vincenza

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide

  3. Music-supported motor training after stroke reveals no superiority of synchronisation in group therapy

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    Floris Tijmen Van Vugt

    2014-05-01

    Full Text Available Background. Music-supported therapy has been shown to be an effective tool for rehabilitation of motor deficits after stroke. A unique feature of music performance is that it is inherently social: music can be played together in synchrony.Aim. The present study explored the potential of synchronised music playing during therapy, asking whether synchronised playing could improve fine motor rehabilitation and mood.Method. Twenty-eight patients in neurological early rehabilitation after stroke with no previous musical background were included. Patients learned to play simple finger exercises and familiar children’s songs on the piano for ten sessions of half an hour. Patients first received three individual therapy sessions and then continued in pairs. The patient pairs were divided into two groups. Patients in one group played synchronously (together group whereas the patients in the other group played one after the other (in-turn group. To assess fine motor skill recovery the patients performed standard clinical tests such as the nine-hole-pegboard test (9HPT and index finger-tapping speed and regularity, and metronome-paced finger tapping. Patients' mood was established using the Profile of Mood States (POMS.Results. Both groups showed improvements in fine motor control. In metronome-paced finger tapping, patients in both groups improved significantly. Mood tests revealed reductions in depression and fatigue in both groups. During therapy, patients in the in-turn group rated their partner as more sympathetic than the together-group in a visual-analogue scale.Conclusions. Our results suggest that music-supported stroke rehabilitation can improve fine motor control and mood not only individually but also in patient pairs. Patients who were playing in turn rather than simultaneously tended to reveal greater improvement in fine motor skill. We speculate that patients in the former group may benefit from the opportunity to learn from observation.

  4. Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells

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    So Young Jung

    2015-09-01

    Full Text Available Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A2. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death.

  5. Improving motor cortico-thalamic communication after stroke using real-time fMRI connectivity-based neurofeedback

    Science.gov (United States)

    Liew, Sook-Lei; Rana, Mohit; Cornelsen, Sonja; de Barros Filho, Marcos Fortunato; Birbaumer, Niels; Sitaram, Ranganatha; Cohen, Leonardo G.; Soekadar, Surjo R.

    2015-01-01

    Background Two thirds of stroke survivors experience motor impairment resulting in long-term disability. The anatomical substrate is often the disruption of cortico-subcortical pathways. It has been proposed that reestablishment of corticosubcortical communication relates to functional recovery. Objective Here, we applied a novel training protocol to augment ipsilesional cortico-subcortical connectivity after stroke. Chronic stroke patients with severe motor impairment were provided online feedback of blood-oxygenation level dependent (BOLD) signal connectivity between cortical and subcortical regions critical for motor function using real-time functional magnetic resonance imaging (rtfMRI) neurofeedback. Results In this proof of principle study, 3 out of 4 patients learned to voluntarily modulate cortico-subcortical connectivity as intended. Conclusions Our results document for the first time the feasibility and safety for patients with chronic stroke and severe motor impairment to self-regulate and augment ipsilesional cortico-subcortical connectivity through neurofeedback using rtfMRI. PMID:26671217

  6. Comparison of Brunnstrom movement therapy and Motor Relearning Program in rehabilitation of post-stroke hemiparetic hand: a randomized trial.

    Science.gov (United States)

    Pandian, Shanta; Arya, Kamal Narayan; Davidson, E W Rajkumar

    2012-07-01

    Motor recovery of the hand usually plateaus in chronic stroke patients. Various conventional and contemporary approaches have been used to rehabilitate the hand post-stroke. However, the evidence for their effectiveness is still limited. To compare the hand therapy protocols based on Brunnstrom approach and motor relearning program in rehabilitation of the hand of chronic stroke patients. Randomized trial. Outpatients attending the occupational therapy department of a rehabilitation institute. 30 post-stroke subjects (35.06 ± 14.52 months) were randomly assigned into two equal groups (Group A and Group B), Outcome Measures: Brunnstrom recovery stages of hand (BRS-H), Fugl-Meyer assessment: wrist and hand (FMA-WH). Group A received Brunnstrom hand manipulation (BHM). BHM is the hand treatment protocol of the Brunnstrom movement therapy, which uses synergies and reflexes to develop voluntary motor control. Group B received the Motor Relearning Program (MRP) based hand protocol. MRP is the practice of specific motor skills, which results in the ability to perform a task. Active practice of context-specific motor task such as reaching and grasping helps regain the lost motor functions. Both the therapy protocols were effective in rehabilitation of the hand (BRS-H; p = 0.003 to 0.004, FMA-WH; p hand motor recovery) (p rehabilitation of the hand in chronic post-stroke patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Decreased Motor Neuron Support by SMA Astrocytes due to Diminished MCP1 Secretion.

    Science.gov (United States)

    Martin, Jasmin E; Nguyen, TrangKimberly T; Grunseich, Christopher; Nofziger, Jonathan H; Lee, Philip R; Fields, Douglas; Fischbeck, Kenneth H; Foran, Emily

    2017-05-24

    Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of the survival of motor neuron 1 ( SMN1 ) gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of SMN protein levels has been shown to mitigate disease manifestations in mice. However, the mechanism by which SMN deficiency in astrocytes may contribute to SMA is unclear and what aspect of astrocyte activity is lacking is unknown. Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that compromise normal function. We show here that SMA astrocyte cultures derived from mouse spinal cord of both sexes are deficient in supporting both WT and SMN-deficient motor neurons derived from male, female, and mixed-sex sources and that this deficiency may be mitigated with secreted factors. In particular, SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus be a new therapeutic approach to SMA. SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction also contributes to the disease in mouse models. Monocyte chemoactive protein 1 (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, we report that MCP1 levels are decreased in SMA mice and that replacement of deficient MCP1 increases differentiation and neurite length of WT and SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel aspect of

  8. Location of lesion determines motor vs. cognitive consequences in patients with cerebellar stroke

    Directory of Open Access Journals (Sweden)

    Catherine J. Stoodley

    2016-01-01

    Full Text Available Cerebellar lesions can cause motor deficits and/or the cerebellar cognitive affective syndrome (CCAS; Schmahmann's syndrome. We used voxel-based lesion-symptom mapping to test the hypothesis that the cerebellar motor syndrome results from anterior lobe damage whereas lesions in the posterolateral cerebellum produce the CCAS. Eighteen patients with isolated cerebellar stroke (13 males, 5 females; 20–66 years old were evaluated using measures of ataxia and neurocognitive ability. Patients showed a wide range of motor and cognitive performance, from normal to severely impaired; individual deficits varied according to lesion location within the cerebellum. Patients with damage to cerebellar lobules III–VI had worse ataxia scores: as predicted, the cerebellar motor syndrome resulted from lesions involving the anterior cerebellum. Poorer performance on fine motor tasks was associated primarily with strokes affecting the anterior lobe extending into lobule VI, with right-handed finger tapping and peg-placement associated with damage to the right cerebellum, and left-handed finger tapping associated with left cerebellar damage. Patients with the CCAS in the absence of cerebellar motor syndrome had damage to posterior lobe regions, with lesions leading to significantly poorer scores on language (e.g. right Crus I and II extending through IX, spatial (bilateral Crus I, Crus II, and right lobule VIII, and executive function measures (lobules VII–VIII. These data reveal clinically significant functional regions underpinning movement and cognition in the cerebellum, with a broad anterior-posterior distinction. Motor and cognitive outcomes following cerebellar damage appear to reflect the disruption of different cerebro-cerebellar motor and cognitive loops.

  9. Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus

    Science.gov (United States)

    DePuy, Seth D.; Stornetta, Ruth L.; Bochorishvili, Genrieta; Deisseroth, Karl; Witten, Ilana; Coates, Melissa; Guyenet, Patrice G.

    2013-01-01

    Summary The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here we test whether these rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons use glutamate as a transmitter in the dorsal motor nucleus of the vagus (DMV). After injecting Cre-dependent AAV2 DIO-Ef1α-channelrhodopsin2(ChR2)-mCherry (AAV2) into the RVLM of dopamine-beta-hydroxylase Cre transgenic mice (DβHCre/0), mCherry was detected exclusively in RVLM-CA neurons. Within the DMV >95% mCherry-immunoreactive (-ir) axonal varicosities were tyrosine hydroxylase-ir and the same proportion were vesicular glutamate transporter 2 (VGLUT2)-ir. VGLUT2-mCherry co-localization was virtually absent when AAV2 was injected into the RVLM of DβHCre/0;VGLUT2flox/flox mice, into the caudal VLM (A1 noradrenergic neuron-rich region) of DβHCre/0 mice or into the raphe of ePetCre/0 mice. Following injection of AAV2 into RVLM of TH-Cre rats, phenylethanolamine N-methyl transferase (PNMT) and VGLUT2 immunoreactivities were highly co-localized in DMV within EYFP-positive or EYFP-negative axonal varicosities. Ultrastructurally, mCherry terminals from RVLM-CA neurons in DβHCre/0 mice made predominantly asymmetric synapses with ChAT-ir DMV neurons. Photostimulation of ChR2-positive axons in DβHCre/0 mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Photostimulation (20 Hz) activated PGNs up to 8 spikes/sec (current clamp). EPSCs were eliminated by tetrodotoxin, reinstated by 4-aminopyridine and blocked by ionotropic glutamate receptor blockers. In conclusion, VGLUT2 is expressed by RVLM-CA (C1) neurons in rats and mice regardless of the presence of AAV2, the C1 neurons activate DMV parasympathetic preganglionic neurons monosynaptically and this connection uses glutamate as an ionotropic transmitter. PMID:23345223

  10. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke.

    Science.gov (United States)

    Khodaparast, Navid; Hays, Seth A; Sloan, Andrew M; Fayyaz, Tabbassum; Hulsey, Daniel R; Rennaker, Robert L; Kilgard, Michael P

    2014-09-01

    Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. During the therapeutic training stage, rats received vagus nerve stimulation paired with each successful trial. All 17 trained rats demonstrated significant contralateral forelimb impairment when performing a bradykinesia assessment task. Forelimb function was recovered completely to prelesion levels when vagus nerve stimulation was delivered during rehab training. Alternatively, intensive rehab training alone (without stimulation) failed to restore function to prelesion levels. Delivering the same amount of stimulation after rehab training did not yield improvements compared with rehab alone. These results demonstrate that vagus nerve stimulation repeatedly paired with successful forelimb movements can improve recovery after motor cortex ischemia and may be a viable option for stroke rehabilitation. © The Author(s) 2014.

  11. Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment.

    Science.gov (United States)

    Matusica, Dusan; Alfonsi, Fabienne; Turner, Bradley J; Butler, Tim J; Shepheard, Stephanie R; Rogers, Mary-Louise; Skeldal, Sune; Underwood, Clare K; Mangelsdorf, Marie; Coulson, Elizabeth J

    2016-02-01

    The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo. © 2016. Published by The Company of Biologists Ltd.

  12. Fractal dimension of EEG activity senses neuronal impairment in acute stroke.

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    Filippo Zappasodi

    Full Text Available The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal properties. Under the hypothesis that the fractal dimension (FD of the electroencephalographic signal (EEG is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD's ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4-10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105 and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures' activities in stroke recovery.

  13. Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

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    Sharma Rakesh

    2004-05-01

    Full Text Available Abstract Functional magnetic resonance imaging (fMRI is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities.

  14. Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

    Science.gov (United States)

    Do-Ha, Dzung; Buskila, Yossi; Ooi, Lezanne

    2018-02-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K + concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

  15. Motor control may support mirror neuron research with new hypotheses and methods. Reply to comments on "Grasping synergies: A motor-control approach to the mirror neuron mechanism"

    Science.gov (United States)

    D'Ausilio, Alessandro; Bartoli, Eleonora; Maffongelli, Laura

    2015-03-01

    We are grateful to all commentators for their insightful commentaries and observations that enrich our proposal. One of our aims was indeed to bridge the gap between fields of research that, progressing independently, are facing similar issues regarding the neural representation of motor knowledge. In this respect, we were pleased to receive feedback from eminent researchers on both the mirror neuron as well as the motor control fields. Their expertise covers animal and human neurophysiology, as well as the computational modeling of neural and behavioral processes. Given their heterogeneous cultural perspectives and research approaches, a number of important open questions were raised. For simplicity we separated these issues into four sections. In the first section we present methodological aspects regarding how synergies can be measured in paradigms investigating the human mirror system. The second section regards the fundamental definition of what exactly synergies might be. The third concerns how synergies can generate testable predictions in mirror neuron research. Finally, the fourth section deals with the ultimate question regarding the function of the mirror neuron system.

  16. Effects of cerebrolysin on motor-neuron-like NSC-34 cells

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    Keilhoff, Gerburg, E-mail: Gerburg.keilhoff@med.ovgu.de [Institute of Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg (Germany); Lucas, Benjamin; Pinkernelle, Josephine; Steiner, Michael [Institute of Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg (Germany); Fansa, Hisham [Department of Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Klinikum Bielefeld, Teutoburger Str. 50, D-33604 Bielefeld (Germany)

    2014-10-01

    Although the peripheral nervous system is capable of regeneration, this capability is limited. As a potential means of augmenting nerve regeneration, the effects of cerebrolysin (CL) – a proteolytic peptide fraction – were tested in vitro on the motor-neuron-like NSC-34 cell line and organotypic spinal cord cultures. Therefore, NSC-34 cells were subjected to mechanical stress by changing media and metabolic stress by oxygen glucose deprivation. Afterwards, cell survival/proliferation using MTT and BrdU-labeling (FACS) and neurite sprouting using ImageJ analysis were evaluated. Calpain-1, Src and α-spectrin protein expression were analyzed by Western blot. In organotypic cultures, the effect of CL on motor neuron survival and neurite sprouting was tested by immunohistochemistry. CL had a temporary anti-proliferative but initially neuroprotective effect on OGD-stressed NSC-34 cells. High-dosed or repeatedly applied CL was deleterious for cell survival. CL amplified neurite reconstruction to limited extent, affected calpain-1 protein expression and influenced calpain-mediated spectrin cleavage as a function of Src expression. In organotypic spinal cord slice cultures, CL was not able to support motor neuron survival/neurite sprouting. Moreover, it hampered astroglia and microglia activities. The data suggest that CL may have only isolated positive effects on injured spinal motor neurons. High-dosed or accumulated CL seemed to have adverse effects in treatment of spinal cord injury. Further experiments are required to optimize the conditions for a safe clinical administration of CL in spinal cord injuries. - Highlights: • Cerebrolysin (CL) is anti-proliferative but initially neuroprotective in OGD-stressed NSC-34 cells. • CL amplified neurite reconstruction of NSC-34 cells. • CL affected calpain-1 expression and calpain-mediated spectrin cleavage as function of Src expression. • In organotypic spinal cord cultures, CL hampered motor neuron survival and

  17. The fugl-meyer assessment of motor recovery after stroke: a critical review of its measurement properties.

    Science.gov (United States)

    Gladstone, David J; Danells, Cynthia J; Black, Sandra E

    2002-09-01

    Measurement of recovery after stroke is becoming increasingly important with the advent of new treatment options under investigation in stroke rehabilitation research. The Fugl-Meyer scale was developed as the first quantitative evaluative instrument for measuring sensorimotor stroke recovery, based on Twitchell and Brunnstrom's concept of sequential stages of motor return in the hemiplegic stroke patient. The Fugl-Meyer is a well-designed, feasible and efficient clinical examination method that has been tested widely in the stroke population. Its primary value is the 100-point motor domain, which has received the most extensive evaluation. Excellent interrater and intrarater reliability and construct validity have been demonstrated, and preliminary evidence suggests that the Fugl-Meyer assessment is responsive to change. Limitations of the motor domain include a ceiling effect, omission of some potentially relevant items, and weighting of the arm more than the leg. Further study should test performance of this scale in specific subgroups of stroke patients and better define its criterion validity, sensitivity to change, and minimal clinically important difference. Based on the available evidence, the Fugl-Meyer motor scale is recommended highly as a clinical and research tool for evaluating changes in motor impairment following stroke.

  18. Sensorimotor experience and verb-category mapping in human sensory, motor and parietal neurons.

    Science.gov (United States)

    Yang, Ying; Dickey, Michael Walsh; Fiez, Julie; Murphy, Brian; Mitchell, Tom; Collinger, Jennifer; Tyler-Kabara, Elizabeth; Boninger, Michael; Wang, Wei

    2017-07-01

    Semantic grounding is the process of relating meaning to symbols (e.g., words). It is the foundation for creating a representational symbolic system such as language. Semantic grounding for verb meaning is hypothesized to be achieved through two mechanisms: sensorimotor mapping, i.e., directly encoding the sensorimotor experiences the verb describes, and verb-category mapping, i.e., encoding the abstract category a verb belongs to. These two mechanisms were investigated by examining neuronal-level spike (i.e. neuronal action potential) activities from the motor, somatosensory and parietal areas in two human participants. Motor and a portion of somatosensory neurons were found to be involved in primarily sensorimotor mapping, while parietal and some somatosensory neurons were found to be involved in both sensorimotor and verb-category mapping. The time course of the spike activities and the selective tuning pattern of these neurons indicate that they belong to a large neural network used for semantic processing. This study is the first step towards understanding how words are processed by neurons. Published by Elsevier Ltd.

  19. Rehabilitation of stroke patients with apraxia: the role of additional cognitive and motor impairments.

    OpenAIRE

    Heugten, C.M. van; Dekker, J.; Deelman, B.G.; Stehmann-Saris, J.C.; Kinebanian, A.

    2000-01-01

    PURPOSE: The present study investigated which additional cognitive and motor impairments were present in stroke patients with apraxia and which of these factors influenced the effects of treatment. METHOD: A group of 33 patients with apraxia were treated according to the guidelines of a therapy programme based on teaching patients strategies to compensate for the presence of apraxia. Patients were treated at occupational therapy departments in general hospitals, rehabilitation centres and nur...

  20. Morphology and intrinsic excitability of regenerating sensory and motor neurons grown on a line micropattern.

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    Ouafa Benzina

    Full Text Available Axonal regeneration is one of the greatest challenges in severe injuries of peripheral nerve. To provide the bridge needed for regeneration, biological or synthetic tubular nerve constructs with aligned architecture have been developed. A key point for improving axonal regeneration is assessing the effects of substrate geometry on neuronal behavior. In the present study, we used an extracellular matrix-micropatterned substrate comprising 3 µm wide lines aimed to physically mimic the in vivo longitudinal axonal growth of mice peripheral sensory and motor neurons. Adult sensory neurons or embryonic motoneurons were seeded and processed for morphological and electrical activity analyses after two days in vitro. We show that micropattern-guided sensory neurons grow one or two axons without secondary branching. Motoneurons polarity was kept on micropattern with a long axon and small dendrites. The micro-patterned substrate maintains the growth promoting effects of conditioning injury and demonstrates, for the first time, that neurite initiation and extension could be differentially regulated by conditioning injury among DRG sensory neuron subpopulations. The micro-patterned substrate impacts the excitability of sensory neurons and promotes the apparition of firing action potentials characteristic for a subclass of mechanosensitive neurons. The line pattern is quite relevant for assessing the regenerative and developmental growth of sensory and motoneurons and offers a unique model for the analysis of the impact of geometry on the expression and the activity of mechanosensitive channels in DRG sensory neurons.

  1. Morphology and intrinsic excitability of regenerating sensory and motor neurons grown on a line micropattern.

    Science.gov (United States)

    Benzina, Ouafa; Cloitre, Thierry; Martin, Marta; Raoul, Cédric; Gergely, Csilla; Scamps, Frédérique

    2014-01-01

    Axonal regeneration is one of the greatest challenges in severe injuries of peripheral nerve. To provide the bridge needed for regeneration, biological or synthetic tubular nerve constructs with aligned architecture have been developed. A key point for improving axonal regeneration is assessing the effects of substrate geometry on neuronal behavior. In the present study, we used an extracellular matrix-micropatterned substrate comprising 3 µm wide lines aimed to physically mimic the in vivo longitudinal axonal growth of mice peripheral sensory and motor neurons. Adult sensory neurons or embryonic motoneurons were seeded and processed for morphological and electrical activity analyses after two days in vitro. We show that micropattern-guided sensory neurons grow one or two axons without secondary branching. Motoneurons polarity was kept on micropattern with a long axon and small dendrites. The micro-patterned substrate maintains the growth promoting effects of conditioning injury and demonstrates, for the first time, that neurite initiation and extension could be differentially regulated by conditioning injury among DRG sensory neuron subpopulations. The micro-patterned substrate impacts the excitability of sensory neurons and promotes the apparition of firing action potentials characteristic for a subclass of mechanosensitive neurons. The line pattern is quite relevant for assessing the regenerative and developmental growth of sensory and motoneurons and offers a unique model for the analysis of the impact of geometry on the expression and the activity of mechanosensitive channels in DRG sensory neurons.

  2. Morphological Characteristics of Motor Neurons Do Not Determine Their Relative Susceptibility to Degeneration in a Mouse Model of Severe Spinal Muscular Atrophy

    Science.gov (United States)

    Mutsaers, Chantal A.; Thomson, Derek; Hamilton, Gillian; Parson, Simon H.; Gillingwater, Thomas H.

    2012-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice – including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA. PMID:23285108

  3. Sideways walk test: Reliability and association with lower limb motor function after stroke.

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    Ng, Shamay S M; Lau, Bobby K C; Law, Gilbert T C; Wom, Choco W K; Liu, Tai-Wa; Tam, Eric W C; Tse, Mimi M Y; Fong, Shirley S M

    2016-10-05

    To investigate (i) the intra-rater, inter-rater and test-retest reliability of sideways walk test times and counts in individuals with stroke; (ii) their correlations with stroke-specific measures of impairment; (iii) the cut-off sideways walk test times and counts between stroke survivors and healthy controls; and (iv) the minimum detectable changes in the sideways walk test times and counts. Cross-sectional study. University-based rehabilitation centre. Twenty-nine older adults with stroke and 32 healthy controls. The sideways walk test was conducted together with Fugl-Meyer motor assessments of the lower extremities, lower limb muscle strength tests, the Five-Times-Sit-To-Stand test, Berg Balance Scale, Timed Up-and-Go test, and Activity-based Confidence and Community Integration Measure questionnaires. The sideways walk test times and counts demonstrated good to excellent intra-rater, inter-rater, and test-retest reliabilities. The sideways walk test times and counts were significantly correlated with motor control and ankle dorsiflexor and plantarflexor strength of the affected leg, balance performance and functional mobility. The cut-off sideways walk test time and count that best discriminated between individuals with stroke and controls were 10.74 s and 8.83 steps, respectively. The minimal detectable change in the sideways walk test time in that situation was 1.85 s, and the count minimum detectable change was 1.12 steps. The sideways walk test is a reliable and easy-to-administer clinical test for assessing sideways walking ability of individuals with chronic stroke.

  4. Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice.

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    Sung-Min Kim

    Full Text Available Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained can affect the loss of motor neurons or cognitive function in an in vivo model of ALS.To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice.Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation.Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation.Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.

  5. Forced Aerobic Exercise Enhances Motor Recovery After Stroke: A Case Report

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    Rosenfeldt, Anson B.; Rasanow, Matthew; Alberts, Jay L.

    2015-01-01

    OBJECTIVE. Previously, we demonstrated that forced aerobic exercise (FE) increases the pattern of neural activation in Parkinson’s disease. We sought to evaluate whether FE, when coupled with repetitive task practice, could promote motor recovery poststroke. METHOD. A 46-yr-old man with ischemic stroke exhibited chronic residual upper-extremity deficits, scoring 35/66 on the Fugl-Meyer Assessment (FMA) at baseline. He completed 24 training sessions comprising 45 min of FE on a motorized stationary bicycle followed by 45 min of upper-extremity repetitive task practice. RESULTS. From baseline to end of treatment, the FMA score improved by 20 points, perceived level of recovery on the Stroke Impact Scale increased by 20 percentage points, and cardiovascular function measured by peak oxygen uptake improved 30%. These improvements persisted 4 wk after the intervention ceased. CONCLUSION. FE may be a safe and feasible rehabilitation approach to augment recovery of motor and nonmotor function while improving aerobic fitness in people with chronic stroke. PMID:26114455

  6. Network feedback regulates motor output across a range of modulatory neuron activity.

    Science.gov (United States)

    Spencer, Robert M; Blitz, Dawn M

    2016-06-01

    Modulatory projection neurons alter network neuron synaptic and intrinsic properties to elicit multiple different outputs. Sensory and other inputs elicit a range of modulatory neuron activity that is further shaped by network feedback, yet little is known regarding how the impact of network feedback on modulatory neurons regulates network output across a physiological range of modulatory neuron activity. Identified network neurons, a fully described connectome, and a well-characterized, identified modulatory projection neuron enabled us to address this issue in the crab (Cancer borealis) stomatogastric nervous system. The modulatory neuron modulatory commissural neuron 1 (MCN1) activates and modulates two networks that generate rhythms via different cellular mechanisms and at distinct frequencies. MCN1 is activated at rates of 5-35 Hz in vivo and in vitro. Additionally, network feedback elicits MCN1 activity time-locked to motor activity. We asked how network activation, rhythm speed, and neuron activity levels are regulated by the presence or absence of network feedback across a physiological range of MCN1 activity rates. There were both similarities and differences in responses of the two networks to MCN1 activity. Many parameters in both networks were sensitive to network feedback effects on MCN1 activity. However, for most parameters, MCN1 activity rate did not determine the extent to which network output was altered by the addition of network feedback. These data demonstrate that the influence of network feedback on modulatory neuron activity is an important determinant of network output and feedback can be effective in shaping network output regardless of the extent of network modulation. Copyright © 2016 the American Physiological Society.

  7. Progressive recruitment of contralesional cortico-reticulospinal pathways drives motor impairment post stroke.

    Science.gov (United States)

    McPherson, Jacob G; Chen, Albert; Ellis, Michael D; Yao, Jun; Heckman, C J; Dewald, Julius P A

    2018-02-19

    Activation of the shoulder abductor muscles in the arm opposite a unilateral brain injury causes involuntary increases in elbow, wrist and finger flexion in the same arm, a phenomenon referred to as the flexion synergy. It has been proposed that flexion synergy expression is related to reduced output from ipsilesional motor cortex and corticospinal pathways. In this human subjects study, we provide evidence that the magnitude of flexion synergy expression is instead related to a progressive, task-dependent recruitment of contralesional cortex. We also provide evidence that recruitment of contralesional cortex may induce excessive activation of ipsilateral reticulospinal descending motor pathways that cannot produce discrete movements, leading to flexion synergy expression. We interpret these findings as an adaptive strategy that preserves low-level motor control at the cost of fine motor control. A hallmark of hemiparetic stroke is the loss of fine motor control in the contralesional arm and hand and the constraint to a grouped movement pattern known as the flexion synergy. In the flexion synergy, increasing shoulder abductor activation drives progressive, involuntary increases in elbow, wrist and finger flexion. The neural mechanisms underlying this phenomenon remain unclear. Here, across 25 adults with moderate to severe hemiparesis following chronic stroke and 18 adults without neurological injury, we test the overall hypothesis that two inter-related mechanisms are necessary for flexion synergy expression: increased task-dependent activation of the intact, contralesional cortex and recruitment of contralesional motor pathways via ipsilateral reticulospinal projections. First, we imaged brain activation in real time during reaching motions progressively constrained by flexion synergy expression. Using this approach, we found that cortical activity indeed shifts towards the contralesional hemisphere in direct proportion to the degree of shoulder abduction loading

  8. GABA Levels Are Decreased After Stroke and GABA Changes During Rehabilitation Correlate With Motor Improvement

    Science.gov (United States)

    Blicher, Jakob Udby; Near, Jamie; Næss-Schmidt, Erhard; Stagg, Charlotte J.; Johansen-Berg, Heidi; Nielsen, Jørgen Feldbæk; Østergaard, Leif; Ho, Yi-Ching Lynn

    2017-01-01

    Background and Objective γ-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the brain and is important in motor learning. We aimed to measure GABA content in primary motor cortex poststroke (using GABA-edited magnetic resonance spectroscopy [MRS]) and in relation to motor recovery during 2 weeks of constraint-induced movement therapy (CIMT). Methods Twenty-one patients (3-12 months poststroke) and 20 healthy subjects were recruited. Magnetic resonance imaging structural T1 and GABA-edited MRS were performed at baseline and after CIMT, and once in healthy subjects. GABA:creatine (GABA:Cr) ratio was measured by GABA-edited MRS. Motor function was measured using Wolf Motor Function Test (WMFT). Results Baseline comparison between stroke patients (n = 19) and healthy subjects showed a significantly lower GABA:Cr ratio in stroke patients (P < .001) even after correcting for gray matter content in the voxel (P < .01) and when expressing GABA relative to N-acetylaspartic acid (NAA; P = .03). After 2 weeks of CIMT patients improved significantly on WMFT, but no consistent change across the group was observed for the GABA:Cr ratio (n = 17). However, the extent of improvement on WMFT correlated significantly with the magnitude of GABA:Cr changes (P < .01), with decreases in GABA:Cr ratio being associated with better improvements in motor function. Conclusions In patients 3 to 12 months poststroke, GABA levels are lower in the primary motor cortex than in healthy subjects. The observed association between GABA and recovery warrants further studies on the potential use of GABA MRS as a biomarker in poststroke recovery. PMID:25055837

  9. Effect of motor imagery therapy on cognitive function of patients with stroke

    Directory of Open Access Journals (Sweden)

    Wei-jun GONG

    2017-07-01

    Full Text Available Objective To explore the rehabilitation effect of motor imagery therapy on cognitive function of stroke patients.  Methods A total of 99 stroke patients with mild to moderate cognitive dysfunction were randomly divided into 3 groups: control group (N = 33, cognitive training group (N = 33 and motor imagery training group (N = 33. All patients received conventional rehabilitation training. Before and after 8-week training, all subjects were assessed with Mini-Mental State Examination (MMSE and Montreal Cognitive Assessment (MoCA. At the same time, event-related potential (ERP was examined to detect P300 latency and amplitude.   Results ompared with before training, MMSE (P = 0.000 and MoCA (P = 0.000 scores were significantly increased, P300 latency was shortened (P = 0.000 and P300 amplitude was increased (P = 0.000 in 3 groups after 8 - week training. There were significant differences among 3 groups on MMSE (P = 0.030 and MoCA (P = 0.013 scores, P300 latency (P = 0.004 and P300 amplitude (P = 0.009 before and after training. Among them, cognitive training group and motor imagery training group had significantly higher MMSE (P = 0.019, 0.021 and MoCA (P = 0.003, 0.031 scores, shorter P300 latency (P = 0.020, 0.003 and higher P300 amplitude (P = 0.003, 0.002 than control group.  Conclusions Motor imagery training can not only improve motor function of stroke patients, but also improve their cognitive function. DOI: 10.3969/j.issn.1672-6731.2017.06.005

  10. Rehabilitation of stroke patients with apraxia: the role of additional cognitive and motor impairments.

    Science.gov (United States)

    van Heugten, C M; Dekker, J; Deelman, B G; Stehmann-Saris, J C; Kinebanian, A

    2000-08-15

    The present study investigated which additional cognitive and motor impairments were present in stroke patients with apraxia and which of these factors influenced the effects of treatment. A group of 33 patients with apraxia were treated according to the guidelines of a therapy programme based on teaching patients strategies to compensate for the presence of apraxia. Patients were treated at occupational therapy departments in general hospitals, rehabilitation centres and nursing homes. The outcome of the strategy training was studied in a pre-post test design; measurements were conducted at baseline and after 12 weeks of therapy. The pretreatment scores of the patients with apraxia were compared to normscores and scores of a control group of patients without apraxia (n = 36) to investigate which impairments are present. The following variables were analysed in order to determine which factors influence outcome: additional neuropsychological deficits (comprehension of language, cognitive impairments due to dementia, neglect and short term memory), level of motor functioning, severity of apraxia and performance on activities of daily living (ADL), and some relevant patient characteristics (gender, age, type of stroke, time since stroke, and location of treatment). The results showed that the presence of apraxia is associated with the presence of additional cognitive and motor impairments. The successful outcome of strategy training was not negatively influenced by cognitive comorbidity. The outcome seemed to be more prominent in patients who were more severely impaired at the start of rehabilitation in terms of the degree of motor impairments, the severity of apraxia and the initial ADL dependence. The ADL observations, however, displayed a ceiling effect, which was taken into account in discussing the results. Demographic variables, especially age, did not predict the outcome of treatment. We suggest that the effect of this training is stronger in more severely

  11. Reciprocal inhibition between motor neurons of the tibialis anterior and triceps surae in humans.

    Science.gov (United States)

    Yavuz, Utku Şükrü; Negro, Francesco; Diedrichs, Robin; Farina, Dario

    2018-01-31

    Motor neurons innervating antagonist muscles receive reciprocal inhibitory afferent inputs in order to facilitate the joint movement in the two directions. The present study investigates the mutual transmission of reciprocal inhibitory afferent inputs between the tibialis anterior (TA) and triceps surae (soleus and medial gastrocnemius) motor units. We assessed this mutual mechanism in large populations of motor units for building a statistical distribution of the inhibition amplitudes during standardized input to the motor neuron pools in order to minimize the effect of modulatory pathways. Single motor unit activities were identified using high-density surface electromyography (HDsEMG) recorded from the TA, soleus (Sol) and medial gastrocnemius (GM) muscles during isometric dorsi- and plantar-flexion. Reciprocal inhibition on the antagonist muscle was elicited by electrical stimulation of the tibial (TN) or common peroneal nerves (CPN). The probability density distributions of reflex strength for each muscle were estimated in order to examine the strength of mutual transmission of reciprocal inhibitory input. The results showed that the strength of reciprocal inhibition in the TA motor units was a 4-fold greater than for the GM and the Sol motor units. This suggests an asymmetric transmission of reciprocal inhibition between ankle extensor and flexor muscles. This asymmetry cannot be explained by differences in motor unit type composition between the investigated muscles since we sampled low-threshold motor units in all cases. Therefore, the differences observed for the strength of inhibition are presumably due to a differential reciprocal spindle afferent input and the relative contribution of non-reciprocal inhibitory pathways.

  12. Effect of electroacupuncture in patients with post-stroke motor aphasia : Neurolinguistic and neuroimaging characteristics.

    Science.gov (United States)

    Chang, Jingling; Zhang, Hua; Tan, Zhongjian; Xiao, Juan; Li, Shuren; Gao, Ying

    2017-02-01

    In this study we investigated the neurolinguistic and neuroimaging characteristics of post-stroke motor aphasia patients. The effects of acupuncture on cortex activation by using magnetic resonance imaging (MRI) in patients with motor aphasia were also studied. In this study 43 patients with motor aphasia after stroke were assessed according to Clinical Rehabilitation Research Center aphasia examination (CRRCAE) for linguistic evaluation and MRI and computed tomography (CT) were used for the analyses of brain lesions. The MRI imaging data were also examined using statistical parametric mapping (SPM8) software. Cortex activation images during acupuncture were analyzed using generalized linear model analysis. The results of MRI and CT showed diverse brain lesion regions of post-stroke motor aphasia including the cortex, subcortex and cortex together with the subcortex. The language-related brain areas are activated by acupuncture including frontal, temporal, parietal and occipital lobes as well as insula, precuneus and other wide range of brain function areas as shown by MRI. Our study showed that the brain lesion regions in post-stroke motor aphasia were not completely consistent with the classical motor speech center. By using MRI our study results suggest that the formation of cognitive language may be involved with the cortical-subcortical functional networks. Acupuncture may be useful for treatment of motor aphasia after stroke.

  13. Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

    Science.gov (United States)

    Murashov, A. K.; Ul Haq, I.; Hill, C.; Park, E.; Smith, M.; Wang, X.; Wang, X.; Goldberg, D. J.; Wolgemuth, D. J.

    2001-01-01

    The p38 stress-activated protein kinase pathway is involved in regulation of phosphorylation of Hsp25, which in turn regulates actin filament dynamic in non-neuronal cells. We report that p38, Hsp25 and Akt signaling pathways were specifically activated in spinal motor neurons after sciatic nerve axotomy. The activation of the p38 kinase was required for induction of Hsp25 expression. Furthermore, Hsp25 formed a complex with Akt, a member of PI-3 kinase pathway that prevents neuronal cell death. Together, our observations implicate Hsp25 as a central player in a complex system of signaling that may both promote regeneration of nerve fibers and prevent neuronal cell death in the injured spinal cord.

  14. Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli.

    Science.gov (United States)

    Tornero, Daniel; Tsupykov, Oleg; Granmo, Marcus; Rodriguez, Cristina; Grønning-Hansen, Marita; Thelin, Jonas; Smozhanik, Ekaterina; Laterza, Cecilia; Wattananit, Somsak; Ge, Ruimin; Tatarishvili, Jemal; Grealish, Shane; Brüstle, Oliver; Skibo, Galina; Parmar, Malin; Schouenborg, Jens; Lindvall, Olle; Kokaia, Zaal

    2017-03-01

    Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Improvement of Gait Symmetry in Patients with Stroke by Motor Imagery.

    Science.gov (United States)

    Pheung-phrarattanatrai, Anuchai; Bovonsunthonchai, Sunee; Heingkaew, Vimonwan; Prayoonwiwat, Naraporn; Chotik-anuchit, Songkram

    2015-06-01

    To investigate effect of gait training with motor imagery (MI) on gait symmetry and self-efficacy offalling in stroke patients. Fourteen stroke patients were categorized in the MI (n = 7) and control (n = 7) groups. They were matched by age range, stroke type, paretic side, time since stroke, and severity. All participants received physical therapy and only the MI group received additional MI training. Both groups were trained for 12 sessions over 1 month. Outcome measurements comprised gait symmetry detecting by theforce distribution measurement platform and self-efficacy offalling testing by the Fall Efficacy Scale-International (FES-I). Both groups were assessed three times:.pre-, intermediate- and post-trainings. Comparisons of all variables between and within groups were tested by Mann-Whitney U test and Friedman ANOVA test, respectively. No significant difference was observed of gait symmetry between MI and control groups. Within group comparison, tendencies of improvement were found in step length and step time symmetry for the MI group. Significant improvements in step length symmetry and FES-I score were found among assessments for the MI group (psymmetry and decreased fear offalling in patients with stroke.

  16. Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus.

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    Matías A Goldin

    2017-08-01

    Full Text Available Different neuronal types within brain motor areas contribute to the generation of complex motor behaviors. A widely studied songbird forebrain nucleus (HVC has been recognized as fundamental in shaping the precise timing characteristics of birdsong. This is based, among other evidence, on the stretching and the "breaking" of song structure when HVC is cooled. However, little is known about the temperature effects that take place in its neurons. To address this, we investigated the dynamics of HVC both experimentally and computationally. We developed a technique where simultaneous electrophysiological recordings were performed during temperature manipulation of HVC. We recorded spontaneous activity and found three effects: widening of the spike shape, decrease of the firing rate and change in the interspike interval distribution. All these effects could be explained with a detailed conductance based model of all the neurons present in HVC. Temperature dependence of the ionic channel time constants explained the first effect, while the second was based in the changes of the maximal conductance using single synaptic excitatory inputs. The last phenomenon, only emerged after introducing a more realistic synaptic input to the inhibitory interneurons. Two timescales were present in the interspike distributions. The behavior of one timescale was reproduced with different input balances received form the excitatory neurons, whereas the other, which disappears with cooling, could not be found assuming poissonian synaptic inputs. Furthermore, the computational model shows that the bursting of the excitatory neurons arises naturally at normal brain temperature and that they have an intrinsic delay at low temperatures. The same effect occurs at single synapses, which may explain song stretching. These findings shed light on the temperature dependence of neuronal dynamics and present a comprehensive framework to study neuronal connectivity. This study, which

  17. Cortical Motor Organization, Mirror Neurons, and Embodied Language: An Evolutionary Perspective

    Directory of Open Access Journals (Sweden)

    Leonardo Fogassi

    2012-11-01

    Full Text Available The recent conceptual achievement that the cortical motor system plays a crucial role not only in motor control but also in higher cognitive functions has given a new perspective also on the involvement of motor cortex in language perception and production. In particular, there is evidence that the matching mechanism based on mirror neurons can be involved in both pho-nological recognition and retrieval of meaning, especially for action word categories, thus suggesting a contribution of an action–perception mechanism to the automatic comprehension of semantics. Furthermore, a compari-son of the anatomo-functional properties of the frontal motor cortex among different primates and their communicative modalities indicates that the combination of the voluntary control of the gestural communication systems and of the vocal apparatus has been the critical factor in the transition from a gestural-based communication into a predominantly speech-based system. Finally, considering that the monkey and human premotor-parietal motor system, plus the prefrontal cortex, are involved in the sequential motor organization of actions and in the hierarchical combination of motor elements, we propose that elements of such motor organization have been exploited in other domains, including some aspects of the syntactic structure of language.

  18. Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

    Science.gov (United States)

    Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

    2017-07-01

    Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

  19. Adult rat motor neurons do not re-establish electrical coupling during axonal regeneration and muscle reinnervation.

    Directory of Open Access Journals (Sweden)

    Morgana Favero

    Full Text Available Gap junctions (GJs between neurons are present in both the newborn and the adult nervous system, and although important roles have been suggested or demonstrated in a number of instances, in many other cases a full understanding of their physiological role is still missing. GJs are expressed in the rodent lumbar cord at birth and mediate both dye and electrical coupling between motor neurons. This expression has been proposed to mediate: (i fast synchronization of motoneuronal spike activity, in turn linked to the process of refinement of neuromuscular connections, and (ii slow synchronization of locomotor-like oscillatory activity. Soon after birth this coupling disappears. Since in the adult rat regeneration of motor fibers after peripheral nerve injury leads to a recapitulation of synaptic refinement at the target muscles, we tested whether GJs between motor neurons are transiently re-expressed. We found that in conditions of maximal responsiveness of lumbar motor neurons (such as no depression by anesthetics, decerebrate release of activity of subsets of motor neurons, use of temporal and spatial summation by antidromic and orthodromic stimulations, testing of large ensembles of motor neurons no firing is observed in ventral root axons in response to antidromic spike invasion of nearby counterparts. We conclude that junctional coupling between motor neurons is not required for the refinement of neuromuscular innervation in the adult.

  20. Single-photon emission computed tomographic findings and motor neuron signs in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Terao, Shin-ichi; Sobue, Gen; Higashi, Naoki; Takahashi, Masahiko; Suga, Hidemichi; Mitsuma, Terunori

    1995-01-01

    123 I-amphetamine-single photon emission computed tomography (SPECT) was performed on 16 patients with amyotrophic lateral sclerosis (ALS) to investigate the correlation between regional cerebral blood flow (rCBF) and upper motor neuron signs. Significant decreased blood flow less than 2 SDs below the mean of controls was observed in the frontal lobe in 4 patients (25%) and in the frontoparietal lobe including the cortical motor area in 4 patients, respectively. The severity of extermity muscular weakness was significantly correlate with decrease in blood flow through the frontal lobe (p<0.05) and through the frontoparietal lobe (p<0.001). A significant correlation was also noted to exist between the severity of bulbar paralysis and decrease in blood flow through the frontoparietal lobe. No correlation, however, was observed between rCBF and severity of spasticity, presence or absence of Babinski's sign and the duration of illness. Although muscular weakness in the limbs and bulbar paralysis are not pure upper motor neuron signs, the observed reduction in blood flow through the frontal or frontoparietal lobes appears to reflect extensive progression of functional or organic lesions of cortical neurons including the motor area. (author)

  1. Beadex Function in the Motor Neurons Is Essential for Female Reproduction in Drosophila melanogaster

    Science.gov (United States)

    Kairamkonda, Subhash; Nongthomba, Upendra

    2014-01-01

    Drosophila melanogaster has served as an excellent model system for understanding the neuronal circuits and molecular mechanisms regulating complex behaviors. The Drosophila female reproductive circuits, in particular, are well studied and can be used as a tool to understand the role of novel genes in neuronal function in general and female reproduction in particular. In the present study, the role of Beadex, a transcription co-activator, in Drosophila female reproduction was assessed by generation of mutant and knock down studies. Null allele of Beadex was generated by transposase induced excision of P-element present within an intron of Beadex gene. The mutant showed highly compromised reproductive abilities as evaluated by reduced fecundity and fertility, abnormal oviposition and more importantly, the failure of sperm release from storage organs. However, no defect was found in the overall ovariole development. Tissue specific, targeted knock down of Beadex indicated that its function in neurons is important for efficient female reproduction, since its neuronal knock down led to compromised female reproductive abilities, similar to Beadex null females. Further, different neuronal class specific knock down studies revealed that Beadex function is required in motor neurons for normal fecundity and fertility of females. Thus, the present study attributes a novel and essential role for Beadex in female reproduction through neurons. PMID:25396431

  2. Spinal cord-specific deletion of the glutamate transporter GLT1 causes motor neuron death in mice.

    Science.gov (United States)

    Sugiyama, Kaori; Tanaka, Kohichi

    2018-03-04

    Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder characterized by the selective loss of motor neurons. The precise mechanisms that cause the selective death of motor neurons remain unclear, but a growing body of evidence suggests that glutamate-mediated excitotoxicity has been considered to play an important role in the mechanisms of motor neuron degeneration in ALS. Reductions in glutamate transporter GLT1 have been reported in animal models of ALS and the motor cortex and spinal cord of ALS patients. However, it remains unknown whether the reduction in GLT1 has a primary role in the induction of motor neuron degeneration in ALS. Here, we generated conditional knockout mice that lacked GLT1 specifically in the spinal cord by crossing floxed-GLT1 mice and Hoxb8-Cre mice. Hoxb8-Cre/GLT1 flox/flox mice showed motor deficits and motor neuron loss. Thus, loss of the glial glutamate transporter GLT1 is sufficient to cause motor neuron death in mice. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Cortical disconnection of the ipsilesional primary motor cortex is associated with gait speed and upper extremity motor impairment in chronic left hemispheric stroke.

    Science.gov (United States)

    Peters, Denise M; Fridriksson, Julius; Stewart, Jill C; Richardson, Jessica D; Rorden, Chris; Bonilha, Leonardo; Middleton, Addie; Gleichgerrcht, Ezequiel; Fritz, Stacy L

    2018-01-01

    Advances in neuroimaging have enabled the mapping of white matter connections across the entire brain, allowing for a more thorough examination of the extent of white matter disconnection after stroke. To assess how cortical disconnection contributes to motor impairments, we examined the relationship between structural brain connectivity and upper and lower extremity motor function in individuals with chronic stroke. Forty-three participants [mean age: 59.7 (±11.2) years; time poststroke: 64.4 (±58.8) months] underwent clinical motor assessments and MRI scanning. Nonparametric correlation analyses were performed to examine the relationship between structural connectivity amid a subsection of the motor network and upper/lower extremity motor function. Standard multiple linear regression analyses were performed to examine the relationship between cortical necrosis and disconnection of three main cortical areas of motor control [primary motor cortex (M1), premotor cortex (PMC), and supplementary motor area (SMA)] and motor function. Anatomical connectivity between ipsilesional M1/SMA and the (1) cerebral peduncle, (2) thalamus, and (3) red nucleus were significantly correlated with upper and lower extremity motor performance (P ≤ 0.003). M1-M1 interhemispheric connectivity was also significantly correlated with gross manual dexterity of the affected upper extremity (P = 0.001). Regression models with M1 lesion load and M1 disconnection (adjusted for time poststroke) explained a significant amount of variance in upper extremity motor performance (R 2  = 0.36-0.46) and gait speed (R 2  = 0.46), with M1 disconnection an independent predictor of motor performance. Cortical disconnection, especially of ipsilesional M1, could significantly contribute to variability seen in locomotor and upper extremity motor function and recovery in chronic stroke. Hum Brain Mapp 39:120-132, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Adult ciliary neurotrophic factor receptors help maintain facial motor neuron choline acetyltransferase expression in vivo following nerve crush.

    Science.gov (United States)

    Lee, Nancy; Rydyznski, Carolyn E; Rasch, Matthew S; Trinh, Dennis S; MacLennan, A John

    2017-04-01

    Exogenous ciliary neurotrophic factor (CNTF) administration promotes the survival of motor neurons in a wide range of models. It also increases the expression of the critical neurotransmitter enzyme choline acetyltransferase (ChAT) by in vitro motor neurons, likely independent of its effects on their survival. We have used the adult mouse facial nerve crush model and adult-onset conditional disruption of the CNTF receptor α (CNTFRα) gene to directly examine the in vivo roles played by endogenous CNTF receptors in adult motor neuron survival and ChAT maintenance, independent of developmental functions. We have previously shown that adult activation of the CreER gene construct in floxed CNTFRα mice depletes this essential receptor subunit in a large subset of motor neurons (and all skeletal muscle, as shown in this study) but has no effect on the survival of intact or lesioned motor neurons, indicating that these adult CNTF receptors play no essential survival role in this model, in contrast to their essential role during embryonic development. Here we show that this same CNTFRα depletion does not affect ChAT labeling in nonlesioned motor neurons, but it significantly increases the loss of ChAT following nerve crush. The data suggest that, although neither motor neuron nor muscle CNTF receptors play a significant, nonredundant role in the maintenance of ChAT in intact adult motor neurons, the receptors become essential for ChAT maintenance when the motor neurons are challenged by nerve crush. Therefore, the data suggest that the receptors act as a critical component of an endogenous neuroprotective mechanism. J. Comp. Neurol. 525:1206-1215, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy.

    Science.gov (United States)

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M; Yang, Ben; Shi, Han; Sze, Christie C; Hong, Benjamin Taige; Su, Susan C; Cantu, Jorge A; Topczewski, Jacek; Crawford, Thomas O; Ko, Chien-Ping; Sumner, Charlotte J; Ma, Long; Ma, Yong-Chao

    2015-04-15

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. Copyright © 2015 the authors 0270-6474/15/356038-13$15.00/0.

  6. Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias.

    Science.gov (United States)

    Foster, Vincent; Oakley, Arthur E; Slade, Janet Y; Hall, Roslyn; Polvikoski, Tuomo M; Burke, Matthew; Thomas, Alan J; Khundakar, Ahmad; Allan, Louise M; Kalaria, Raj N

    2014-09-01

    Dementia associated with cerebrovascular disease is common. It has been reported that ∼30% of elderly patients who survive stroke develop delayed dementia (post-stroke dementia), with most cases being diagnosed as vascular dementia. The pathological substrates associated with post-stroke or vascular dementia are poorly understood, particularly those associated with executive dysfunction. Three separate yet interconnecting circuits control executive function within the frontal lobe involving the dorsolateral prefrontal cortex, anterior cingulate cortex and the orbitofrontal cortex. We used stereological methods, along with immunohistological and related cell morphometric analysis, to examine densities and volumes of pyramidal neurons of the dorsolateral prefrontal cortex, anterior cingulate cortex and orbitofrontal cortex in the frontal lobe from a total of 90 elderly subjects (age range 71-98 years). Post-mortem brain tissues from post-stroke dementia and post-stroke patients with no dementia were derived from our prospective Cognitive Function After Stroke study. We also examined, in parallel, samples from ageing controls and similar age subjects pathologically diagnosed with Alzheimer's disease, mixed Alzheimer's disease and vascular dementia, and vascular dementia. We found pyramidal cell volumes in layers III and V in the dorsolateral prefrontal cortex of post-stroke and vascular dementia and, of mixed and Alzheimer's disease subjects to be reduced by 30-40% compared to post-stroke patients with no dementia and controls. There were no significant changes in neuronal volumes in either the anterior cingulate or orbitofrontal cortices. Remarkably, pyramidal neurons within the orbitofrontal cortex were also found to be smaller in size when compared to those in the other two neocortical regions. To relate the cell changes to cognitive function, we noted significant correlations between neuronal volumes and total CAMCOG, orientation and memory scores and clinical

  7. Dysfunctional mitochondrial Ca2+ handling in mutant SOD1 mouse models of fALS: integration of findings from motor neuron somata and motor terminals

    Directory of Open Access Journals (Sweden)

    Ellen F Barrett

    2014-07-01

    Full Text Available Abundant evidence indicates that mitochondrial dysfunction and Ca2+ dysregulation contribute to the muscle denervation and motor neuron death that occur in mouse models of familial amyotrophic lateral sclerosis (fALS. This perspective considers measurements of mitochondrial function and Ca2+ handling made in both motor neuron somata and motor nerve terminals of SOD1-G93A mice at different disease stages. These complementary studies are integrated into a model of how mitochondrial dysfunction disrupts handling of stimulation-induced Ca2+ loads in presymptomatic and end-stages of this disease. Also considered are possible mechanisms underlying the findings that some treatments that preserve motor neuron somata fail to postpone degeneration of motor axons and terminals.

  8. Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.

    Directory of Open Access Journals (Sweden)

    Ximena Paez-Colasante

    Full Text Available In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA, lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN. Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+ as a driver on the same mice, and another report that used Hb9(Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+ SMA mice relative to ChAT(Cre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

  9. The impact of recovery of visuo-spatial neglect on motor recovery of the upper paretic limb after stroke.

    Directory of Open Access Journals (Sweden)

    Tanja C W Nijboer

    Full Text Available The aim of the current study was to investigate the longitudinal relationship between improvements of synergism and strength of the upper paretic limb and severity of visuo-spatial neglect during the first 52 weeks post-stroke. The longitudinal association between severity of VSN and motor impairment using Fugl Meyer motor score and Motricity Index of the arm was measured in an intensive repeated measurement design including 18 measurement sessions for each subject. Neglect was assessed using the letter cancellation test applied in a prospective cohort of 101 ischemic, first-ever, hemispheric stroke patients. All time-dependent measures were taken weekly, starting within 14 days post-stroke. From week 10 to 20 biweekly measurements are obtained. The longitudinal relationship of (biweekly time on improvement of motor functions and severity of neglect was investigated using random coefficient analysis and trend analyses. Fifty-one of the 101 stroke patients showed neglect at stroke onset. Less improvement of synergism and strength of the upper paretic limb was associated with more severe neglect. This association was most pronounced in the first 10 weeks post-stroke. The seemingly suppressive effect of neglect on upper-limb motor recovery appears to take place mainly during spontaneous neurological recovery of first 10 weeks post-stroke. This finding suggests that damage to large-scale white matter tracts of especially the perceptual-attention networks suppress recovery of other networks at distance in the brain suggesting a common underlying mechanism.

  10. Impact of internal capsule lesions on outcome of motor hand function at one year post-stroke

    NARCIS (Netherlands)

    Schiemanck, Sven K.; Kwakkel, Gert; Post, Marcel W. M.; Kappelle, L. Jaap; Prevo, Arie J. H.

    2008-01-01

    OBJECTIVE: To investigate the association between damage to different levels of the corticofugal tract and long-term hand motor recovery. DESIGN: Prospective cohort study. PATIENTS: Seventy-five first-ever middle cerebral artery stroke survivors. METHODS: Hand motor function was assessed with the

  11. Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex.

    Directory of Open Access Journals (Sweden)

    Naohiko Okabe

    Full Text Available Task-specific rehabilitative training is commonly used for chronic stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to photothrombotic stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction.

  12. Effects of truncal motor imagery practice on trunk performance, functional balance, and daily activities in acute stroke

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    Priyanka Shah

    2016-01-01

    Full Text Available Background: Motor imagery is beneficial to treat upper and lower limbs motor impairments in stroke patients, but the effects of imagery in the trunk recovery have not been reported. Hence, the aim is to test the effects of truncal motor imagery practice on trunk performance, functional balance, and daily activities in acute stroke patients. Methods: This pilot randomized clinical trial was conducted in acute stroke unit. Acute stroke patients with hemodynamic stability, aged between 30 and 70 years, first time stroke, and scoring <20 on trunk impairment scale (TIS were included in the study. Patients in the experimental group practiced trunk motor imagery in addition to physical training. Control group was given conventional physical therapy. The treatment intensity was 90 min/day, 6 days a week for 3 weeks duration. Trunk control test, TIS, brunel balance assessment (BBA, and Barthel index (BI were considered as the outcome measures. Results: Among 23 patients included in the study, 12 and 11 patients, respectively, in the control and experimental groups completed the intervention. Repeated measures ANOVA, i.e., timeFNx01 group factor analysis and effect size showed statistically significant improvements (P = 0.001 in the scores of TIS (1.64, BBA (1.83, and BI (0.67. Conclusion: Motor imagery of trunk in addition to the physical practice showed benefits in improving trunk performance, functional balance, and daily living in acute stroke.

  13. Characterizing relationships of DTI, fMRI, and motor recovery in stroke rehabilitation utilizing brain-computer interface technology.

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    Song, Jie; Young, Brittany M; Nigogosyan, Zack; Walton, Leo M; Nair, Veena A; Grogan, Scott W; Tyler, Mitchell E; Farrar-Edwards, Dorothy; Caldera, Kristin E; Sattin, Justin A; Williams, Justin C; Prabhakaran, Vivek

    2014-01-01

    The relationship of the structural integrity of white matter tracts and cortical activity to motor functional outcomes in stroke patients is of particular interest in understanding mechanisms of brain structural and functional changes while recovering from stroke. This study aims to probe these underlying mechanisms using diffusion tensor imaging (DTI) and fMRI measures. We examined the structural integrity of the posterior limb of the internal capsule (PLIC) using DTI and corticomotor activity using motor-task fMRI in stroke patients who completed up to 15 sessions of rehabilitation therapy using Brain-Computer Interface (BCI) technology. We hypothesized that (1) the structural integrity of PLIC and corticomotor activity are affected by stroke; (2) changes in structural integrity and corticomotor activity following BCI intervention are related to motor recovery; (3) there is a potential relationship between structural integrity and corticomotor activity. We found that (1) the ipsilesional PLIC showed significantly decreased fractional anisotropy (FA) values when compared to the contralesional PLIC; (2) lower ipsilesional PLIC-FA values were significantly associated with worse motor outcomes (i.e., ipsilesional PLIC-FA and motor outcomes were positively correlated.); (3) lower ipsilesional PLIC-FA values were significantly associated with greater ipsilesional corticomotor activity during impaired-finger-tapping-task fMRI (i.e., ipsilesional PLIC-FA and ipsilesional corticomotor activity were negatively correlated), with an overall bilateral pattern of corticomotor activity observed; and (4) baseline FA values predicted motor recovery assessed after BCI intervention. These findings suggest that (1) greater vs. lesser microstructural integrity of the ipsilesional PLIC may contribute toward better vs. poor motor recovery respectively in the stroke-affected limb and demand lesser vs. greater cortical activity respectively from the ipsilesional motor cortex; and that (2

  14. [HE Xingwei's exploration and experience in the pathogenesis and treatment of motor impairment of the trunk after stroke].

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    Zhang, Peng; Hu, Songfeng; He, Fan; Fang, Jinying; Wang, Qiang; He, Xingwei

    2017-02-12

    In the paper, it is introduced professor HE Xingwei 's recognition on the pathogenesis and professor HE 's experience in the treatment of the motor impairment of the trunk after stroke. Professor He believes that the motor impairment of the trunk after stroke is the essential factor affecting the rehabilitation in stroke. The motor impairment of the trunk after stroke results from brain marrow damage and spiritual impairment. Hence, regaining the consciousness and promoting the circulation of the governor vessel are the basic principles of the treatment, named regulating the mind and controlling qi , benefiting qi and warming yang , tonifying the kidney and filling up the essence, and promoting the circulation of the governor vessel. Those four therapeutic methods are equally important. Acupuncture, moxibusiton and herbal medicine are applied in combination in the treatment. Additionally, the psychotherapy and rehabilitation are the accessory therapies.

  15. Motor recovery by improvement of limb-kinetic apraxia in a chronic stroke patient.

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    Jang, Sung Ho

    2013-01-01

    We report on a chronic stroke patient who showed motor recovery by improvement of limb-kinetic apraxia (LKA) after undergoing intensive rehabilitation for a period of one month, which was demonstrated by diffusion tensor tractography (DTT) and transcranial magnetic stimulation (TMS). A 50-year-old male patient presented with severe paralysis of the left extremities at the onset of thalamic hemorrhage. At thirty months after onset, the patient exhibited moderate weakness of his left upper and lower extremities. In addition, he exhibited a slow, clumsy, and mutilated movement pattern during grasp-release movements of his left hand. During a one-month period of intensive rehabilitation, which was started at thrity months after onset, the patient showed 22% motor recovery of the left extremities. The slow, clumsy, and mutilated movement pattern of the left hand almost disappeared. DTTs of the corticospinal tract (CST) in both hemispheres originated from the cerebral cortex, including the primary motor cortex, and passed along the known CST pathway. The DTT of the right CST was located anterior to the old hemorrhagic lesion. TMS study performed at thirty and thirty-one months after onset showed normal and similar findings for motor evoked potential in terms of latency and amplitude of the left hand muscle. We think that the motor weakness of the left extremities in this patient was mainly ascribed to LKA and that most of the motor recovery during a one-month period of rehabilitation was attributed to improvement of LKA.

  16. Recovery-related indicators of motor network plasticity according to impairment severity after stroke.

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    Lee, J; Park, E; Lee, A; Chang, W H; Kim, D-S; Kim, Y-H

    2017-10-01

    Brain connectivity analysis has been widely used to investigate brain plasticity and recovery-related indicators of patients with stroke. However, results remain controversial because of interindividual variability of initial impairment and subsequent recovery of function. In this study, we aimed to investigate the differences in network plasticity and motor recovery-related indicators according to initial severity. We divided participants (16 males and 14 females, aged 54.2 ± 12.0 years) into groups of different severity by Fugl-Mayer Assessment score, i.e. moderate (50-84), severe (20-49) and extremely severe (impairment groups. Longitudinal resting-state functional magnetic resonance imaging data were acquired at 2 weeks and 3 months after onset. The differences in network plasticity and recovery-related indicators between groups were investigated using network distance and graph measurements. As the level of impairment increased, the network balance was more disrupted. Network balance, interhemispheric connectivity and network efficiency were recovered at 3 months only in the moderate impairment group. However, this was not the case in the extremely severe impairment group. A single connection strength between the ipsilesional primary motor cortex and ventral premotor cortex was implicated in the recovery of motor function for the extremely severe impairment group. The connections of the ipsilesional primary motor cortex-ventral premotor cortex were positively associated with motor recovery as the patients were more severely impaired. Differences in plasticity and recovery-related indicators of motor networks were noted according to impairment severity. Our results may suggest meaningful implications for recovery prediction and treatment strategies in future stroke research. © 2017 EAN.

  17. Techniques for studying protein trafficking and molecular motors in neurons.

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    Feng, Shanxi; Arnold, Don B

    2016-09-01

    This review focused on techniques that facilitated the visualization of protein trafficking. In the mid-1990s the cloning of GFP allowed fluorescently tagged proteins to be expressed in cells and then visualized in real time. This advance allowed a glimpse, for the first time, of the complex system within cells for distributing proteins. It quickly became apparent, however, that time-lapse sequences of exogenously expressed GFP-labeled proteins can be difficult to interpret. Reasons for this include the relatively low signal that comes from moving proteins and high background rates from stationary proteins and other sources, as well as the difficulty of identifying the origins and destinations of specific vesicular carriers. In this review a range of techniques that have overcome these issues to varying degrees was reviewed and the insights into protein trafficking that they have enabled were discussed. Concentration will be on neurons, as they are highly polarized and, thus, their trafficking systems tend to be accessible for study. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Effects of repetitive transcranial magnetic stimulation on masseter motor-neuron pool excitability.

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    Huang, Huang; Liu, Wei Cai; Song, Yu Han

    2017-01-01

    Repetitive transcranial magnetic stimulation (rTMS) has been widely used to modulate the excitability of the cortical control of limbs muscles, but rarely in the cortical control of human masseter muscles. This study aims to investigate the effects of rTMS on masseter motor-neuron pool excitability in humans. A total of 20 healthy participants were selected and received a total of three rTMS sessions involving stimulation of the right masseter-motor complex: one session of 10-Hz rTMS, one session of 1-Hz rTMS and one session of sham rTMS at an intensity of 80% of the active motor threshold (AMT). The masseter AMT, motor-evoked potentials (MEPs), cortical-silent period (CSP), and short-interval intracortical inhibition (SICI) were measured before and after each rTMS session. The masseter SICI was significantly decreased following 10-Hz rTMS, with no significant changes in AMT, MEPs or CSP. No significant differences in masseter AMT, MEPs, CSP or SICI were observed in either the 1-Hz, or sham rTMS groups. The present findings demonstrate that high-frequency rTMS increases masseter motor-neuron pool excitability. Copyright © 2016. Published by Elsevier Ltd.

  19. Process Extension from Embryonic Stem Cell-Derived Motor Neurons through Synthetic Extracellular Matrix Mimics

    Science.gov (United States)

    McKinnon, Daniel Devaud

    This thesis focuses on studying the extension of motor axons through synthetic poly(ethylene glycol) PEG hydrogels that have been modified with biochemical functionalities to render them more biologically relevant. Specifically, the research strategy is to encapsulate embryonic stem cell-derived motor neurons (ESMNs) in synthetic PEG hydrogels crosslinked through three different chemistries providing three mechanisms for dynamically tuning material properties. First, a covalently crosslinked, enzymatically degradable hydrogel is developed and exploited to study the biophysical dynamics of axon extension and matrix remodeling. It is demonstrated that dispersed motor neurons require a battery of adhesive peptides and growth factors to maintain viability and extend axons while those in contact with supportive neuroglial cells do not. Additionally, cell-degradable crosslinker peptides and a soft modulus mimicking that of the spinal cord are requirements for axon extension. However, because local degradation of the hydrogel results in a cellular environment significantly different than that of the bulk, enzymatically degradable peptide crosslinkers were replaced with reversible covalent hydrazone bonds to study the effect of hydrogel modulus on axon extension. This material is characterized in detail and used to measure forces involved in axon extension. Finally, a hydrogel with photocleavable linkers incorporated into the network structure is exploited to explore motor axon response to physical channels. This system is used to direct the growth of motor axons towards co-cultured myotubes, resulting in the formation of an in vitro neural circuit.

  20. The Effect of Aerobic Exercise on Neuroplasticity within the Motor Cortex following Stroke.

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    Kate Murdoch

    Full Text Available Aerobic exercise is associated with enhanced plasticity in the motor cortex of healthy individuals, but the effect of aerobic exercise on neuroplasticity following a stroke is unknown.The aim of this study was to compare corticomotoneuronal excitability and neuroplasticity in the upper limb cortical representation following a single session of low intensity lower limb cycling, or a rest control condition.We recruited chronic stroke survivors to take part in three experimental conditions in a randomised, cross-over design. Corticomotoneuronal excitability was examined using transcranial magnetic stimulation to elicit motor evoked potentials in the affected first dorsal interosseus muscle. Following baseline measures, participants either cycled on a stationary bike at a low exercise intensity for 30 minutes, or remained resting in a seated position for 30 minutes. Neuroplasticity within the motor cortex was then examined using an intermittent theta burst stimulation (iTBS paradigm. During the third experimental condition, participants cycled for the 30 minutes but did not receive any iTBS.Twelve participants completed the study. We found no significant effect of aerobic exercise on corticomotoneuronal excitability when compared to the no exercise condition (P > 0.05 for all group and time comparisons. The use of iTBS did not induce a neuroplastic-like response in the motor cortex with or without the addition of aerobic exercise.Our results suggest that following a stroke, the brain may be less responsive to non-invasive brain stimulation paradigms that aim to induce short-term reorganisation, and aerobic exercise was unable to induce or improve this response.

  1. Dopamine control of pyramidal neuron activity in the primary motor cortex via D2 receptors

    Directory of Open Access Journals (Sweden)

    Clément eVitrac

    2014-02-01

    Full Text Available The primary motor cortex (M1 is involved in fine voluntary movements control. Previous studies have shown the existence of a dopamine (DA innervation in M1 of rats and monkeys that could directly modulate M1 neuronal activity. However, none of these studies have described the precise distribution of DA terminals within M1 functional region nor have quantified the density of this innervation. Moreover, the precise role of DA on pyramidal neuron activity still remains unclear due to conflicting results from previous studies regarding D2 effects on M1 pyramidal neurons.In this study we assessed in mice the neuroanatomical characteristics of DA innervation in M1 using unbiased stereological quantification of dopamine transporter-immunostained fibers. We demonstrated for the first time in mice that DA innervates the deep layers of M1 targeting preferentially the forelimb representation area of M1. To address the functional role of the DA innervation on M1 neuronal activity, we performed electrophysiological recordings of single neurons activity in vivo and pharmacologically modulated D2 receptors activity. Local D2 receptors activation by quinpirole enhanced pyramidal neurons spike firing rate without changes in spike firing pattern. Altogether, these results indicate that DA innervation in M1 can increase neuronal activity through D2 receptors activation and suggest a potential contribution to the modulation of fine forelimb movement. Given the demonstrated role for DA in fine motor skill learning in M1, our results suggest that altered D2 modulation of M1 activity may be involved in the pathophysiology of movement disorders associated with disturbed DA homeostasis.

  2. Loss of neuron-astroglial interaction rapidly induces protective CNTF expression after stroke in mice

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    Kang, Seong Su; Keasey, Matthew P.; Cai, Jun; Hagg, Theo

    2012-01-01

    Ciliary neurotrophic factor (CNTF) is a potent neural cytokine with very low expression in the CNS, predominantly by astrocytes. CNTF increases rapidly and greatly following traumatic or ischemic injury. Understanding the underlying mechanisms would help to design pharmacological treatments to increase endogenous CNTF levels for neuroprotection. Here, we show that astroglial CNTF expression in the adult mouse striatum is increased two-fold within 1 hour and increases up to >30 fold over two weeks following a focal stroke caused by a transient middle cerebral artery occlusion (MCAO). Selective neuronal loss caused by intrastriatal injection of quinolinic acid resulted in a comparable increase. Co-cultured neurons reduced CNTF expression in astrocytes which was prevented by light trypsinization. RGD blocking peptides induced CNTF expression which was dependent on transcription. Astroglial CNTF expression was not affected by diffusible neuronal molecules or by neurotransmitters. The transient ischemia does not seem to directly increase CNTF, as intrastriatal injection of an ischemic solution or exposure of naive mice or cultured cells to severe hypoxia had minimal effects. Inflammatory mechanisms were probably also not involved, as intrastriatal injection of pro-inflammatory cytokines (IFNγ, IL6) in naive mice had no or small effects, and anti-inflammatory treatments did not diminish the increase in CNTF after MCAO. CNTF−/− mice had more extensive tissue loss and similar astrocyte activation after MCAO than their wildtype littermates. These data suggest that contact-mediated integrin signaling between neurons and astrocytes normally represses CNTF expression and that neuronal dysfunction causes a rapid protective response by the CNS. PMID:22764235

  3. Contrasting effects of cerebrospinal fluid from motor neuron disease patients on the survival of primary motor neurons cultured with or without glia.

    Science.gov (United States)

    Barber, Siân C; Wood-Allum, Clare A; Sargsyan, Siranush A; Walsh, Theresa; Cox, Laura E; Monk, Peter N; Shaw, Pamela J

    2011-07-01

    Motor neuronal (MN) degeneration in motor neuron disease (MND) often starts focally before spreading to neighbouring MN populations, suggesting soluble factors may contribute to disease propagation. Whether cerebrospinal fluid (CSF) from MND patients contains such factors has been difficult to prove. We aimed to determine the effect of glia on the response of MNs to CSF from MND patients. Primary rat spinal MNs grown in mono-culture or cocultured with glia were exposed to CSF from patients (MND-CSF) or controls (Con-CSF) and survival measured by cell counting. In mono-culture both MND-CSF and Con-CSF reduced MN survival with MND-CSF reducing MN survival by less than Con-CSF. In coculture MN survival was unchanged by exposure to MND-CSF while exposure to Con-CSF improved MN survival. In separate experiments, murine MNs grown in mono-culture and stressed by growth factor withdrawal were partially rescued by the application of monocyte chemoattractant protein-1 (MCP-1), a trophic factor previously found to be elevated in MND-CSF. Our results suggest that MND-CSF may contain factors harmful to MNs as well as factors protective of MNs, the interplay of which is altered by the presence of glial cells. These preliminary results further emphasize the importance of MN environment to MN health.

  4. Robotic measurement of arm movements after stroke establishes biomarkers of motor recovery.

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    Krebs, Hermano I; Krams, Michael; Agrafiotis, Dimitris K; DiBernardo, Allitia; Chavez, Juan C; Littman, Gary S; Yang, Eric; Byttebier, Geert; Dipietro, Laura; Rykman, Avrielle; McArthur, Kate; Hajjar, Karim; Lees, Kennedy R; Volpe, Bruce T

    2014-01-01

    Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R(2) of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.

  5. Decoding of motor intentions from epidural ECoG recordings in severely paralyzed chronic stroke patients

    Science.gov (United States)

    Spüler, M.; Walter, A.; Ramos-Murguialday, A.; Naros, G.; Birbaumer, N.; Gharabaghi, A.; Rosenstiel, W.; Bogdan, M.

    2014-12-01

    Objective. Recently, there have been several approaches to utilize a brain-computer interface (BCI) for rehabilitation with stroke patients or as an assistive device for the paralyzed. In this study we investigated whether up to seven different hand movement intentions can be decoded from epidural electrocorticography (ECoG) in chronic stroke patients. Approach. In a screening session we recorded epidural ECoG data over the ipsilesional motor cortex from four chronic stroke patients who had no residual hand movement. Data was analyzed offline using a support vector machine (SVM) to decode different movement intentions. Main results. We showed that up to seven hand movement intentions can be decoded with an average accuracy of 61% (chance level 15.6%). When reducing the number of classes, average accuracies up to 88% can be achieved for decoding three different movement intentions. Significance. The findings suggest that ipsilesional epidural ECoG can be used as a viable control signal for BCI-driven neuroprosthesis. Although patients showed no sign of residual hand movement, brain activity at the ipsilesional motor cortex still shows enough intention-related activity to decode different movement intentions with sufficient accuracy.

  6. Robotic Measurement of Arm Movements After Stroke Establishes Biomarkers of Motor Recovery

    Science.gov (United States)

    Krebs, Hermano I.; Krams, Michael; Agrafiotis, Dimitris K.; DiBernardo, Allitia; Chavez, Juan C.; Littman, Gary S.; Yang, Eric; Byttebier, Geert; Dipietro, Laura; Rykman, Avrielle; McArthur, Kate; Hajjar, Karim; Lees, Kennedy R.; Volpe, Bruce T.

    2015-01-01

    Background and Purpose Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. Methods In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. Results Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R2 of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). Conclusions These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency. PMID:24335224

  7. Effect of a Task-Oriented Rehabilitation Program on Upper Extremity Recovery Following Motor Stroke

    Science.gov (United States)

    Winstein, Carolee J.; Wolf, Steven L.; Dromerick, Alexander W.; Lane, Christianne J.; Nelsen, Monica A.; Lewthwaite, Rebecca; Cen, Steven Yong; Azen, Stanley P.

    2016-01-01

    IMPORTANCE Clinical trials suggest that higher doses of task-oriented training are superior to current clinical practice for patients with stroke with upper extremity motor deficits. OBJECTIVE To compare the efficacy of a structured, task-oriented motor training program vs usual and customary occupational therapy (UCC) during stroke rehabilitation. DESIGN, SETTING, AND PARTICIPANTS Phase 3, pragmatic, single-blind randomized trial among 361 participants with moderate motor impairment recruited from 7 US hospitals over 44 months, treated in the outpatient setting from June 2009 to March 2014. INTERVENTIONS Structured, task-oriented upper extremity training (Accelerated Skill Acquisition Program[ASAP]; n = 119); dose-equivalent occupational therapy (DEUCC; n = 120); or monitoring-only occupational therapy (UCC; n = 122). The DEUCC group was prescribed 30 one-hour sessions over 10 weeks; the UCC group was only monitored, without specification of dose. MAIN OUTCOMES AND MEASURES The primary outcome was 12-month change in log-transformed Wolf Motor Function Test time score (WMFT, consisting of a mean of 15 timed arm movements and hand dexterity tasks). Secondary outcomes were change in WMFT time score (minimal clinically important difference [MCID] = 19 seconds) and proportion of patients improving ≥25 points on the Stroke Impact Scale (SIS) hand function score (MCID = 17.8 points). RESULTS Among the 361 randomized patients (mean age, 60.7 years; 56% men; 42% African American; mean time since stroke onset, 46 days), 304 (84%) completed the 12-month primary outcome assessment; in intention-to-treat analysis, mean group change scores (log WMFT, baseline to 12 months) were, for the ASAP group, 2.2 to 1.4 (difference, 0.82); DEUCC group, 2.0 to 1.2 (difference, 0.84); and UCC group, 2.1 to 1.4 (difference, 0.75), with no significant between-group differences (ASAP vs DEUCC:0.14; 95% CI, −0.05 to 0.33; P = .16; ASAP vs UCC: −0.01; 95% CI, −0.22 to 0.21; P = .94; and

  8. Knockdown of Pnpla6 protein results in motor neuron defects in zebrafish

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    Yang Song

    2013-03-01

    Mutations in patatin-like phospholipase domain containing 6 (PNPLA6, also known as neuropathy target esterase (NTE or SPG39, cause hereditary spastic paraplegia (HSP. Although studies on animal models, including mice and Drosophila, have extended our understanding of PNPLA6, its roles in neural development and in HSP are not clearly understood. Here, we describe the generation of a vertebrate model of PNPLA6 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio. Pnpla6 knockdown resulted in developmental abnormalities and motor neuron defects, including axon truncation and branching. The phenotypes in pnpla6 knockdown morphants were rescued by the introduction of wild-type, but not mutant, human PNPLA6 mRNA. Our results also revealed the involvement of BMP signaling in pnpla6 knockdown phenotypes. Taken together, these results demonstrate an important role of PNPLA6 in motor neuron development and implicate overexpression of BMP signaling as a possible mechanism underlying the developmental defects in pnpla6 morphants.

  9. Message banking: Perceptions of persons with motor neuron disease, significant others and clinicians.

    Science.gov (United States)

    Oosthuizen, Imke; Dada, Shakila; Bornman, Juan; Koul, Rajinder

    2017-07-31

    Message banking is an intervention strategy that has the potential to facilitate effective communication for people with motor neuron disease when their condition deteriorates to the extent that they cannot communicate using natural speech. The aim of the current study was to determine and compare the perceptions on message banking of three stakeholder groups, namely, persons with motor neuron disease, their significant others and speech-language pathologists. A comparative group survey design was used. Participants listened to a short presentation about message banking, after which they individually completed a questionnaire. Although most participants reported that they had never heard of message banking, all were interested in it. The survey results revealed statistically significant differences between the various groups of stakeholders regarding the relevance of message banking and types of messages to bank. The study concluded that there is limited awareness about message banking amongst all participant groups.

  10. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

    Science.gov (United States)

    Scekic-Zahirovic, Jelena; Oussini, Hajer El; Mersmann, Sina; Drenner, Kevin; Wagner, Marina; Sun, Ying; Allmeroth, Kira; Dieterlé, Stéphane; Sinniger, Jérôme; Dirrig-Grosch, Sylvie; René, Frédérique; Dormann, Dorothee; Haass, Christian; Ludolph, Albert C; Lagier-Tourenne, Clotilde; Storkebaum, Erik; Dupuis, Luc

    2017-06-01

    Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.

  11. Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

    Science.gov (United States)

    2015-08-01

    To perform crucial and extensive pre-clinical studies to enable an investigational new drug (IND) application with the Food and Drug Administration...investigational new drug (IND) application with the Food and Drug Administration (FDA) for the approval to move the use of intramuscular GDNF delivery...function has been shown in acute models of motor neuron injury and in transgenic mouse models of ALS using various delivery strategies by a number

  12. Caregiver bodywork: family members' experiences of caring for a person with motor neurone disease.

    Science.gov (United States)

    Ray, Robin A; Street, Annette F

    2006-10-01

    This paper reports a study of how family members caring for people living with motor neurone disease managed the deteriorating body, their own bodywork and the associated emotional labour. People living with the neurodegenerative condition of motor neurone disease face the prospect of dying in 3-5 years from progressive loss of voluntary muscle mass and function, culminating in respiratory failure. Theories concerning the body in illness have been used to illustrate patient perspectives; however, family caregivers' experiences of the body have been neglected. An ethnographic case study was undertaken with 18 primary family caregivers and six peripheral caregivers. Primary caregivers participated over 10 months in three face-to-face, semi-structured interviews which included mapping their support networks using ecomaps. Observational data were also recorded as field notes. Peripheral caregivers were interviewed once during the same time period. The data were generated between 2003 and 2004. Informal caregiving requires engagement in various aspects of bodywork. Three body concepts were identified: the visible body--how the disease affected the patient and caregivers; the dependent body--the resulting care requirements; and the social body--how living with motor neurone disease affected their social support networks. The visible body is a continual reminder of the ravages of the disease, while the dependent body demands physical and emotional care. Social interactions decline over time, depriving family caregivers of the much needed support for sustaining their commitment to the bodywork required in caregiving. The demands of bodywork for family caregivers are increased by the continual presence of emotional labour as they seek to implement the best way to support their relative with motor neurone disease. Nurses and allied healthcare workers need to assess each family situation, asking appropriate questions to establish the most appropriate interventions to

  13. Damage to the medial motor system in stroke patients with motor neglect

    Directory of Open Access Journals (Sweden)

    Raffaella eMigliaccio

    2014-06-01

    Full Text Available Background and objectives. Motor neglect (MN is a clinically important condition whereby patients with unilateral brain lesions fail to move their contralateral limbs, despite normal muscle strength, reflexes, and sensation. MN has been associated with various lesion sites, including the parietal and frontal cortex, the internal capsule, the lenticulostriate nuclei, and the thalamus. In the present study, we explored the hypothesis that MN depends on a dysfunction of the medial motor system by performing a detailed anatomical analysis in four patients with MN.Methods. Ten patients participated in the study: four with MN, four with left visual neglect but without MN, and three patients with left hemiplegia without MN. We used specific scales for clinical and neuropsychological assessment. We drew the lesion borders directly onto the original brain images of each patient, and plotted the lesions on anatomical atlases for grey and white matter. Results. Lesion locations were highly heterogeneous in our MN patients, and included frontal and parietal sites, basal ganglia and white matter. The only consistently damaged structure across all MN patients was the cingulum bundle, a major pathway of the medial motor system important for motor initiative, and a key connection with limbic structures crucial for motivational aspects of actions. Three MN patients with additional damage to lateral fronto-parietal networks had also signs of contralesional visual neglect. The cingulum bundle was intact in all the control patients with visual neglect or hemiplegia.Conclusions. Cingulum damage may induce MN through unilateral dysfunction of the medial motor system. Additional lateral fronto-parietal dysfunction can result in the association with visual neglect.

  14. Brain MR Imaging in Patients with Lower Motor Neuron-Predominant Disease.

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    Spinelli, Edoardo G; Agosta, Federica; Ferraro, Pilar M; Riva, Nilo; Lunetta, Christian; Falzone, Yuri M; Comi, Giancarlo; Falini, Andrea; Filippi, Massimo

    2016-08-01

    Purpose To investigate the patterns of cortical thinning and white matter tract damage in patients with lower motor neuron (LMN)-predominant disease compared with healthy control subjects and those with classic amyotrophic lateral sclerosis (ALS) and to evaluate the relationship between brain structural changes and clinical and cognitive features in these patients. Materials and Methods This study was approved by the local ethical committee, and written informed consent was obtained from all subjects before enrollment. Twenty-eight patients with LMN-predominant disease were compared with 55 patients with ALS and 56 healthy control subjects. Patients underwent a clinical and neuropsychological assessment and T1-weighted and diffusion-tensor magnetic resonance (MR) imaging. Surface-based morphometry was used to assess cortical thickness. Tract-based spatial statistics and tractography were used to study white matter tract damage. Results Patients with LMN-predominant disease did not show differences compared with healthy control subjects in cortical thickness and diffusion-tensor MR imaging metrics. Patients with ALS showed cortical thinning of the motor-related cortices and a distributed involvement of the prefrontal, temporal, and parietal gyri (P motor and extramotor tracts compared with control subjects and patients with LMN-predominant disease (tract-based spatial statistics: P disease, cognitive deficits correlated with alterations in diffusivity in the left cingulum (r = -0.66, P = .01) and superior longitudinal fasciculus (r = -0.65, P = .05). Conclusion Motor and extramotor cortical thinning and diffusion-tensor MR imaging alterations were specific for motor neuron disease phenotypes, with clinically overt upper motor neuron involvement. However, the lack of significant differences in cortical thickness between subjects with LMN-predominant disease and those with ALS and cognitive deficits associated with alterations in diffusivity in patients with LMN

  15. Small GSK-3 Inhibitor Shows Efficacy in a Motor Neuron Disease Murine Model Modulating Autophagy.

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    Estefanía de Munck

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive motor neuron degenerative disease that has no effective treatment up to date. Drug discovery tasks have been hampered due to the lack of knowledge in its molecular etiology together with the limited animal models for research. Recently, a motor neuron disease animal model has been developed using β-N-methylamino-L-alanine (L-BMAA, a neurotoxic amino acid related to the appearing of ALS. In the present work, the neuroprotective role of VP2.51, a small heterocyclic GSK-3 inhibitor, is analysed in this novel murine model together with the analysis of autophagy. VP2.51 daily administration for two weeks, starting the first day after L-BMAA treatment, leads to total recovery of neurological symptoms and prevents the activation of autophagic processes in rats. These results show that the L-BMAA murine model can be used to test the efficacy of new drugs. In addition, the results confirm the therapeutic potential of GSK-3 inhibitors, and specially VP2.51, for the disease-modifying future treatment of motor neuron disorders like ALS.

  16. Computational Analysis of Pharyngeal Swallowing Mechanics in Patients with Motor Neuron Disease: A Pilot Investigation.

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    Garand, K L; Schwertner, Ryan; Chen, Amy; Pearson, William G

    2018-04-01

    Swallowing impairment (dysphagia) is a common sequela in patients with motor neuron disease (MND). The purpose of this retrospective, observational pilot investigation was to characterize how pharyngeal swallowing mechanics are impacted in patients with MND using a comparison with healthy, non-dysphagic control group. Computational analysis of swallowing mechanics (CASM) was used to determine covariate biomechanics of pharyngeal swallowing from videofluoroscopic assessment in 15 patients with MND and 15 age- and sex-matched healthy controls. Canonical variant analysis with post hoc discriminate function analysis (DFA) was performed on coordinate data mapping functional muscle groups underlying pharyngeal swallowing. Differences in swallowing mechanics associated with group (MND; control), motor neuron predominance (upper; lower), onset (bulbar; spinal), and swallow task (thin, pudding) were evaluated and visualized. Pharyngeal swallowing mechanics differed significantly in patients with MND compared with healthy controls (D = 2.01, p mechanics by motor neuron predominance (D = 5.03, p mechanics of patients with MND differ from and are more heterogeneous than healthy controls. These findings suggest patients with MND may compensate reductions in pharyngeal shortening and tongue base retraction by extending the head and neck and increasing hyolaryngeal excursion. This work and further CASM investigations will lead to further insights into development and evaluation of targeted clinical treatments designed to prolong safe and efficient swallowing function in patients with MND.

  17. iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development

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    Irene Faravelli

    2014-10-01

    Full Text Available Motor neuron diseases (MNDs are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs and/or lower motor neurons (LMNs. The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS, while the most common infantile MND is represented by spinal muscular atrophy (SMA. No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders.

  18. Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice.

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    Sato, Shigeto; Uchihara, Toshiki; Fukuda, Takahiro; Noda, Sachiko; Kondo, Hiromi; Saiki, Shinji; Komatsu, Masaaki; Uchiyama, Yasuo; Tanaka, Keiji; Hattori, Nobutaka

    2018-02-12

    Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62. The number and size of these inclusions were gradually increased in neurites rather than soma with aging. These inclusions may facilitate peripheral failures. As a result, DA neuron loss and motor dysfunction including the hindlimb defect were observed in 120-week-old mice. P62 aggregates derived from an autophagic defect might serve as "seeds" and can potentially be cause of LB formation.

  19. The effects of combined repetitive transcranial magnetic stimulation and transcranial direct current stimulation on motor function in patients with stroke.

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    Kwon, Tae Gun; Park, Eunhee; Kang, Chung; Chang, Won Hyuk; Kim, Yun-Hee

    2016-11-22

    Both transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), when provided to stroke patients in combination with motor training, enhance therapeutic efficacy and motor function. However, the majority of previous studies have only examined a single treatment modality. The authors investigated the modulating influence of combination dual-mode brain stimulation upon bihemispheric stimulation with motor training in stroke patients. Twenty stroke patients with hemiparesis underwent five randomly arranged sessions of diverse combinations of rTMS and tDCS. We applied cathodal or anodal tDCS over the contralesional primary motor cortex (cM1) and 10 Hz rTMS over the ipsilesional primary motor cortex (iM1) in a simultaneous or preconditioning method including sham stimulation. Immediately after dual-mode stimulation, sequential hand motor training was performed for 5 minutes. The total pulses of rTMS and the duration of tDCS and motor training were the same for all sessions. Cortical excitability and sequential motor performance were evaluated before and after each session. Motor function and corticomotor excitability following simultaneous stimulation via cathodal tDCS over the cM1 combined with 10 Hz rTMS over the iM1 were significantly increased after the intervention, with significantly greater motor improvement than seen with other treatment conditions (P motor performance in stroke patients than other combination methods. This result seemed to be related to effective modulation of interhemispheric imbalance of cortical excitability by dual-mode stimulation.

  20. Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy.

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    Dhruv Sareen

    Full Text Available Spinal muscular atrophy (SMA is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC lines generated from two Type I SMA subjects-one produced with lentiviral constructs and the second using a virus-free plasmid-based approach-recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients.

  1. Effect of Different Mental Imagery Speeds on the Motor Performance: Investigation of the Role of Mirror Neurons

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    Sajad Parsaei

    2017-09-01

    Conclusion: The results of this study showed that mirror neurons within the premotor cortex are an important neural mechanism in the brain activity pattern, which causes the effectiveness of imagery in the improvement of motor skills.  

  2. Rapid Integration of Artificial Sensory Feedback during Operant Conditioning of Motor Cortex Neurons.

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    Prsa, Mario; Galiñanes, Gregorio L; Huber, Daniel

    2017-02-22

    Neuronal motor commands, whether generating real or neuroprosthetic movements, are shaped by ongoing sensory feedback from the displacement being produced. Here we asked if cortical stimulation could provide artificial feedback during operant conditioning of cortical neurons. Simultaneous two-photon imaging and real-time optogenetic stimulation were used to train mice to activate a single neuron in motor cortex (M1), while continuous feedback of its activity level was provided by proportionally stimulating somatosensory cortex. This artificial signal was necessary to rapidly learn to increase the conditioned activity, detect correct performance, and maintain the learned behavior. Population imaging in M1 revealed that learning-related activity changes are observed in the conditioned cell only, which highlights the functional potential of individual neurons in the neocortex. Our findings demonstrate the capacity of animals to use an artificially induced cortical channel in a behaviorally relevant way and reveal the remarkable speed and specificity at which this can occur. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Reliability and Validity of the Timed Up and Go Test With a Motor Task in People With Chronic Stroke.

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    Chan, Peggy P; Si Tou, Joyce I; Tse, Mimi M; Ng, Shamay S

    2017-11-01

    To examine (1) the intra-rater, interrater, and test-retest reliabilities of the timed Up and Go test with a motor task (TUG motor ) in terms of the number of steps taken in the test and completion time in a population with chronic stroke; (2) the relation between stroke-specific impairments and the number of steps taken in the test and the completion time; (3) the minimum detectable change in TUG motor times; and (4) the cutoff time that best discriminates the performance of people with stroke from that of older adults without stroke. Cross-sectional study. University-based rehabilitation center. A sample (N=65) of chronic stroke survivors (n=33) and healthy older adults (n=32). Not applicable. TUG motor times and number of steps taken; Fugl-Meyer Assessment for the Lower Extremities score; handheld dynamometer measurements of hip abductor, knee flexor and extensor, and ankle dorsiflexor and plantar flexor muscle strength; 5-times sit-to-stand test time, Berg Balance Scale score; conventional timed Up and Go test time, and Activities-specific Balance Confidence scale and Community Integration Measure questionnaire scores. The TUG motor completion times and number of steps demonstrated excellent intra-rater, interrater, and test-retest reliabilities. The TUG motor times correlated significantly with the Fugl-Meyer Assessment for the Lower Extremities and Berg Balance Scale scores, with hip abductor, knee flexor, ankle dorsiflexor and plantar flexor strength on the paretic side, with 5-times sit-to-stand test times, and with times on the conventional timed Up and Go test. The minimum detectable change in TUG motor time was 3.53 seconds in stroke survivors. A TUG motor cutoff time of 13.49 seconds was found to best discriminate the performance of stroke survivors from that of older adults without stroke. The TUG motor is a reliable, valid, and easy-to-administer clinical tool for assessing advanced functional mobility after a stroke. Copyright © 2017 American

  4. Dual-tDCS Enhances Online Motor Skill Learning and Long-Term Retention in Chronic Stroke Patients

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    Lefebvre, S.; Laloux, P.; Peeters, A.; Desfontaines, P.; Jamart, J.; Vandermeeren, Y.

    2013-01-01

    Background: Since motor learning is a key component for stroke recovery, enhancing motor skill learning is a crucial challenge for neurorehabilitation. Transcranial direct current stimulation (tDCS) is a promising approach for improving motor learning. The aim of this trial was to test the hypothesis that dual-tDCS applied bilaterally over the primary motor cortices (M1) improves online motor skill learning with the paretic hand and its long-term retention. Methods: Eighteen chronic stroke patients participated in a randomized, cross-over, placebo-controlled, double bind trial. During separate sessions, dual-tDCS or sham dual-tDCS was applied over 30 min while stroke patients learned a complex visuomotor skill with the paretic hand: using a computer mouse to move a pointer along a complex circuit as quickly and accurately as possible. A learning index involving the evolution of the speed/accuracy trade-off was calculated. Performance of the motor skill was measured at baseline, after intervention and 1 week later. Results: After sham dual-tDCS, eight patients showed performance worsening. In contrast, dual-tDCS enhanced the amount and speed of online motor skill learning compared to sham (p dual-tDCS (n = 10) than after sham (n = 3). More importantly, 1 week later, online enhancement under dual-tDCS had translated into superior long-term retention (+44%) compared to sham (+4%). The improvement generalized to a new untrained circuit and to digital dexterity. Conclusion: A single-session of dual-tDCS, applied while stroke patients trained with the paretic hand significantly enhanced online motor skill learning both quantitatively and qualitatively, leading to successful long-term retention and generalization. The combination of motor skill learning and dual-tDCS is promising for improving post-stroke neurorehabilitation. PMID:23316151

  5. The effects of cognitive versus motor demands on postural performance and weight bearing asymmetry in patients with stroke.

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    Negahban, Hossein; Ebrahimzadeh, Masoome; Mehravar, Mohammad

    2017-10-17

    While several studies have investigated the interaction between postural control and secondary cognitive tasks in stroke patients, little is known about the influence of secondary motor task on postural control in these patients. The current research was designed to further examine dual-task performance by comparing the effects of cognitive versus motor dual-tasks on postural performance and weight bearing asymmetry (WBA) in stroke patients (n=23) relative to healthy, matched controls (n=22). All participants stood on dual-force plate under 5 conditions: (1) free standing; (2) simple cognitive task (easy Stroop) while standing; (3) difficult cognitive task (difficult Stroop) while standing; (4) simple motor task (holding a tray while a cylinder lying on its flat side) while standing; and (5) difficult motor task (holding a tray while a cylinder lying on its round side) while standing. The center of pressure (COP) measures was greater in stroke patients than healthy controls. Also, the WBA of the patients was greater than the controls. The COP measures increased when moving from single-task to cognitive dual-task conditions. No significant effect of motor dual-tasking was seen when moving from single-task to motor dual-task conditions. However, in contrast to cognitive dual-tasking, stroke patients and healthy controls employed different strategies during simultaneous performance of postural and motor tasks. It can be suggested that performing a motor task while standing requires greater attentional resources compared to performing a cognitive task while standing and this resulted in greater dual-task interference on motor performance in the stroke patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Motor deficit outcome in patients with stroke in the neurology unit of the Befelatanana University Hospital in Antananarivo.

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    Razafindrasata, R S; Rasaholiarison, N F; Razafimahefa, J; Tehindrazanarivelo, A D

    2017-11-01

    A stroke is the sudden onset of focal neurological deficits presumed to have mecanism vascular and is the leading cause of acquired motor disability in adults. To improve stroke management, we examined the motor disability of patients presenting with stroke, their course, and its determinant factors. This retrospective descriptive study reviewed case records from the neurology unit of the Befelatanana University Hospital from january to december 2015. We included all patients who had a stroke with motor impairment of any upper or lower limbs, with or without computed tomography of the brain, that is, 227 (36.50 %) of the 622 patients admitted to the neurology unit. The mean age of onset was 55.41 years with a sex-ratio 1.16. Predominantly, we found perforating artery strokes (51.54 %), ischemic strokes (36.12 %), and right limb location deficits (50.22 %). Stroke patients were managed with physical therapy from the beginning of the acute stage, that is, from the admission (77.53 %). Two third of the motor deficits were steady (67.84 %), with a median NIHSS=8 and MRS=4 at hospital discharge. The mortality rate was 8.37 % (6.60 % during the first week and 1.77 % after that). We found no significant determinant factors. Hospital mortality decreased during the study. The lack of overcoming of motor disability was due to the short follow-up period, which included only the acute stage. These findings point out the utility of a neurovascular unit (UNV) for reducing disabilities and developing a network for stroke management during the acute stage in Madagascar.

  7. The motor neuron response to SMN1 deficiency in spinal muscular atrophy.

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    Kang, Peter B; Gooch, Clifton L; McDermott, Michael P; Darras, Basil T; Finkel, Richard S; Yang, Michele L; Sproule, Douglas M; Chung, Wendy K; Kaufmann, Petra; de Vivo, Darryl C

    2014-05-01

    The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). Sixty-two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (-6.32 μV/year, P = 0.10), and stable CMAP amplitude. The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. Copyright © 2013 Wiley Periodicals, Inc.

  8. Grasping synergies: A motor-control approach to the mirror neuron mechanism

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    D'Ausilio, Alessandro; Bartoli, Eleonora; Maffongelli, Laura

    2015-03-01

    The discovery of mirror neurons revived interest in motor theories of perception, fostering a number of new studies as well as controversies. In particular, the degree of motor specificity with which others' actions are simulated is highly debated. Human corticospinal excitability studies support the conjecture that a mirror mechanism encodes object-directed goals or low-level kinematic features of others' reaching and grasping actions. These interpretations lead to different experimental predictions and implications for the functional role of the simulation of others' actions. We propose that the representational granularity of the mirror mechanism cannot be any different from that of the motor system during action execution. Hence, drawing from motor control models, we propose that the building blocks of the mirror mechanism are the relatively few motor synergies explaining the variety of hand functions. The recognition of these synergies, from action observation, can be potentially very robust to visual noise and thus demonstrate a clear advantage of using motor knowledge for classifying others' action.

  9. Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy.

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    Sison, Samantha L; Patitucci, Teresa N; Seminary, Emily R; Villalon, Eric; Lorson, Christian L; Ebert, Allison D

    2017-09-01

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Motor-auditory-visual integration: The role of the human mirror neuron system in communication and communication disorders

    OpenAIRE

    Le Bel, Ronald M.; Pineda, Jaime A.; Sharma, Anu

    2009-01-01

    The mirror neuron system (MNS) is a trimodal system composed of neuronal populations that respond to motor, visual, and auditory stimulation, such as when an action is performed, observed, heard or read about. In humans, the MNS has been identified using neuro-imaging techniques (such as fMRI and mu suppression in the EEG). It reflects an integration of motor-auditory-visual information processing related to aspects of language learning including action understanding and recognition. Such int...

  11. Effect of lower limb rehabilitation robot on lower limb motor function of hemiplegic patients after stroke

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    Jian-liang LU

    2017-07-01

    Full Text Available Objective To observe the rehabilitation effect of lower limb rehabilitation robot training on the lower limb motor function of hemiplegic patients after stroke. Methods A total of 60 stroke patients (duration < 6 months accepted conventional rehabilitation training combined with body weight support treadmill training (BWSTT group, N = 30 or conventional rehabilitation training combined with lower limb rehabilitation robot training (Robot group, N = 30. Fugl - Meyer Assessment Scale for Lower Extremity (FMA-LE was used to evaluate lower limb motor function. Berg Balance Scale (BBS was used to evaluate balance function. Lower limb rehabilitation robot torque feedback system was used to evaluate lower limb muscle strength. All evaluations were performed before and after 8-week training.   Results Compared with before training, the FMA-LE score (P = 0.000, BBS score (P = 0.000, hemiplegic side of hip joint feedback torque value (HJTV, P = 0.000 and knee joint feedback torque value (KJTV, P = 0.000 were increased in both groups after 8-week training. Compared with BWSTT group, the hemiplegic side of HJTV (P = 0.000 and KJTV (P = 0.000 were increased in Robot group after 8-week training, while the FMA-LE score (P = 0.118 and BBS score (P = 0.159 had no statistically significant difference between 2 groups.  Conclusions The lower limb rehabilitation robot or body weight support treadmill training combined with conventional rehabilitation training could improve the lower limb motor function of hemiplegic patients after stroke. The lower limb rehabilitation robot training was better than body weight support treadmill training on the recovery of lower limb muscle strength. DOI: 10.3969/j.issn.1672-6731.2017.05.004  

  12. Upper Extremity Motor Impairments and Microstructural Changes in Bulbospinal Pathways in Chronic Hemiparetic Stroke

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    Meriel Owen

    2017-06-01

    Full Text Available Following hemiparetic stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement, or abnormal limb synergies, which can negatively impact functional use of the paretic arm. One hypothesis for the expression of these synergies is an increased dependence on bulbospinal pathways such as the rubrospinal (RubST tract and especially the reticulospinal (RetST tracts, which co-activate multiple muscles of the shoulder, elbow, wrist, and fingers. Despite indirect evidence supporting this hypothesis in humans poststroke, it still remains unclear whether it is correct. Therefore, we used high-resolution diffusion tensor imaging (DTI to quantify white matter microstructure in relation to severity of arm synergy and hand-related motor impairments. DTI was performed on 19 moderately to severely impaired chronic stroke individuals and 15 healthy, age-matched controls. In stroke individuals, compared to controls, there was significantly decreased fractional anisotropy (FA and significantly increased axial and radial diffusivity in bilateral corona radiata and body of the corpus callosum. Furthermore, poststroke, the contralesional (CL RetST FA correlated significantly with both upper extremity (UE synergy severity (r = −0.606, p = 0.003 and hand impairment (r = −0.609, p = 0.003. FA in the ipsilesional RubST significantly correlated with hand impairment severity (r = −0.590, p = 0.004. For the first time, we separately evaluate RetST and RubST microstructure in chronic stroke individuals with UE motor impairment. We demonstrate that individuals with the greatest UE synergy severity and hand impairments poststroke have the highest FA in the CL RetST a pattern consistent with increased myelination and suggestive of neuroplastic reorganization. Since the RetST pathway microstructure, in particular, is sensitive to abnormal joint coupling and hand-related motor

  13. Succinate-induced neuronal mitochondrial fission and hexokinase II malfunction in ischemic stroke: Therapeutical effects of kaempferol.

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    Wu, Bin; Luo, Hong; Zhou, Xu; Cheng, Cai-Yi; Lin, Lin; Liu, Bao-Lin; Liu, Kang; Li, Ping; Yang, Hua

    2017-09-01

    Mitochondrial dysfunction is known as one of causative factors in ischemic stroke, leading to neuronal cell death. The present work was undertaken to investigate whether succinate induces neuron apoptosis by regulating mitochondrial morphology and function. In neurons, oxygen-glucose deprivation induced succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation, leading to mitochondrial fission. Kaempferol inhibited mitochondrial fission and maintained mitochondrial HK-II through activation of Akt, and thereby protected neurons from succinate-mediated ischemi injury. Knockdown of Akt2 with siRNA diminished the effect of kaempferol, indicating that kaempferol suppressed dynamin-related protein 1 (Drp1) activation and promoted HK-II mitochondrial binding dependently on Akt. Moreover, we demonstrated that kaempferol potentiated autophagy during oxygen and glucose deprivation, contributing to protecting neuron survival against succinate insult. In vivo, oral administration of kaempferol in mice attenuated the infract volume after ischemic and reperfusion (I/R) injury and reproduced the similar mitochondrial protective effect in the brain infract area. This study indicates that succinate accumulation plays a pivotal role in I/R injury-induced neuronal mitochondrial dysfunction, and suggests that modulation of Drp1 phosphorylation might be potential therapeutic strategy to protect neuron mitochondrial integrity and treat ischemic stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. The relationships of motor-evoked potentials to hand dexterity, motor function, and spasticity in chronic stroke patients: a transcranial magnetic stimulation study.

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    Cakar, Engin; Akyuz, Gulseren; Durmus, Oguz; Bayman, Levent; Yagci, Ilker; Karadag-Saygi, Evrim; Gunduz, Osman Hakan

    2016-12-01

    The standardization of patient evaluation and monitoring methods has a special importance in evaluating the effectiveness of therapeutic methods using drugs or rehabilitative techniques in stroke rehabilitation. The aim of this study was to investigate the relationships between clinical instruments and transcranial magnetic stimulation (TMS)-evoked neurophysiological parameters in stroke patients. This study included 22 chronic post-stroke patients who were clinically assessed using the Motricity Index (MI), finger-tapping test (FTT), Motor Activity Log (MAL) 28, Brunnstrom motor staging and Ashworth Scale (ASH). Motor-evoked potential (MEP) latency and amplitude, resting motor threshold (rMT) and central motor conduction time (CMCT) were measured with TMS. Shorter MEP-latency, shorter CMCT, higher motor-evoked potential amplitude, and diminished rMT exhibited significant correlations with clinical measures evaluating motor stage, dexterity, and daily life functionality. rMT exhibited a negative correlation with hand and lower extremity Brunnstrom stages (r = -0.64, r = -0.51, respectively), MI score (r = -0.48), FTT score (r = -0.69), and also with amount of use scale and quality of movement scale of MAL 28 scores (r = -0.61, r = -0.62, respectively). Higher MEP amplitude and diminished rMT showed positive correlations with reduced ASH score (r = -0.65, r = 0.44, respectively). The TMS-evoked neurophysiologic parameters including MEP latency, amplitude, rMT and CMCT generally have positive correlation with clinical measures which evaluate motor stage, dexterity and daily life functionality. Additionally, spasticity has also remarkable relationships with MEP amplitude and rMT. These results suggest that TMS-evoked neurophysiological parameters were useful measures for monitoring post-stroke patients.

  15. Prevalence of ocular motor cranial nerve palsy and associations following stroke

    Science.gov (United States)

    Rowe, F

    2011-01-01

    Aim Occurrence of ocular motor cranial nerve palsies (OMCNP), following stroke, has not been reported in relation to the type of OMCNP seen and in relation to brain area affected by stroke. The aim of this study was to identify all patients referred with suspected visual impairment to establish the presence and type of OMCNP. Methods Prospective, observation study with standardised referral and assessment forms across 20 sites. Visual assessment included visual acuity measurement, visual field assessment, ocular alignment, and movement and visual inattention assessment. Multicentre ethics approval and informed patient consent was obtained. Results In total, 915 patients were recruited with mean age of 69.18 years (SD 14.19). Altogether, 498 patients (54%) were diagnosed with ocular motility abnormalities. Of these, 89 patients (18%) had OMCNP. Unilateral third nerve palsy was present in 23 patients (26%), fourth nerve palsy in 14 patients (16%), and sixth nerve palsy in 52 patients (58%). Out of these, 44 patients had isolated OMCNP and 45 had OMCNP combined with other ocular motility abnormalities. Location of stroke was reported mainly in cerebellum, brain stem, thalamus, and internal and external capsules. Treatment was provided for each case including prisms, occlusion, typoscope, scanning exercises, and refraction. Conclusions OMCNP account for 18% of eye movement abnormalities in this stroke sub-population. Sixth CNP was most common, followed by third and fourth CNP. Half were isolated and half combined with other eye movement abnormality. Most were treated with prisms or occlusion. The reported brain area affected by stroke was typically the cerebellum, brain stem, and diencephalic structures. PMID:21475314

  16. (--Epigallocatechin gallate attenuates NADPH-d/nNOS expression in motor neurons of rats following peripheral nerve injury

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    Tseng Chi-Yu

    2011-06-01

    Full Text Available Abstract Background Oxidative stress and large amounts of nitric oxide (NO have been implicated in the pathophysiology of neuronal injury and neurodegenerative disease. Recent studies have shown that (--epigallocatechin gallate (EGCG, one of the green tea polyphenols, has potent antioxidant effects against free radical-mediated lipid peroxidation in ischemia-induced neuronal damage. The purpose of this study was to examine whether EGCG would attenuate neuronal expression of NADPH-d/nNOS in the motor neurons of the lower brainstem following peripheral nerve crush. Thus, young adult rats were treated with EGCG (10, 25, or 50 mg/kg, i.p. 30 min prior to crushing their hypoglossal and vagus nerves for 30 seconds (left side, at the cervical level. The treatment (pre-crush doses of EGCG was continued from day 1 to day 6, and the animals were sacrificed on days 3, 7, 14 and 28. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d histochemistry and neuronal nitric oxide synthase (nNOS immunohistochemistry were used to assess neuronal NADPH-d/nNOS expression in the hypoglossal nucleus and dorsal motor nucleus of the vagus. Results In rats treated with high dosages of EGCG (25 or 50 mg/kg, NADPH-d/nNOS reactivity and cell death of the motor neurons were significantly decreased. Conclusions The present evidence indicated that EGCG can reduce NADPH-d/nNOS reactivity and thus may enhance motor neuron survival time following peripheral nerve injury.

  17. Schwann Cells Transduced with a Lentiviral Vector Encoding Fgf-2 Promote Motor Neuron Regeneration Following Sciatic Nerve Injury

    NARCIS (Netherlands)

    Allodi, I.; Mecollari, V.; Gonzalez-Perez, F.; Eggers, R.; Hoyng, S.; Verhaagen, J.; Navarro, X.; Udina, E.

    2014-01-01

    Fibroblast growth factor 2 (FGF-2) is a trophic factor expressed by glial cells and different neuronal populations. Addition of FGF-2 to spinal cord and dorsal root ganglia (DRG) explants demonstrated that FGF-2 specifically increases motor neuron axonal growth. To further explore the potential

  18. Schwann cells transduced with a lentiviral vector encoding Fgf-2 promote motor neuron regeneration following sciatic nerve injury

    NARCIS (Netherlands)

    Allodi, Ilary; Mecollari, Vasil; González-Pérez, Francisco; Eggers, R.; Hoyng, S.; Verhaagen, J.; Navarro, Xavier; Udina, Esther

    2014-01-01

    Fibroblast growth factor 2 (FGF-2) is a trophic factor expressed by glial cells and different neuronal populations. Addition of FGF-2 to spinal cord and dorsal root ganglia (DRG) explants demonstrated that FGF-2 specifically increases motor neuron axonal growth. To further explore the potential

  19. Motor-Auditory-Visual Integration: The Role of the Human Mirror Neuron System in Communication and Communication Disorders

    Science.gov (United States)

    Le Bel, Ronald M.; Pineda, Jaime A.; Sharma, Anu

    2009-01-01

    The mirror neuron system (MNS) is a trimodal system composed of neuronal populations that respond to motor, visual, and auditory stimulation, such as when an action is performed, observed, heard or read about. In humans, the MNS has been identified using neuroimaging techniques (such as fMRI and mu suppression in the EEG). It reflects an…

  20. Motor function recovery of people of mature years after stroke by means of physical rehabilitation

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    T.E. Khristova

    2013-02-01

    Full Text Available The results of applying the complex technology of physical rehabilitation are described for patients with cerebral ischemic stroke during the phase of in-patient rehabilitation. The experiment involved 36 male patients aged 45-50 years. The rehabilitation program included treatment by changing position, complex of therapeutic gymnastics (based on sanogenetic approach to the problem of motor function recovery in accordance with the stages of postnatal ontogenesis, magnetic therapy, thermotherapy of large joints of the affected extremities. Findings show that the use of the mentioned methods of treatment leads to increase of the range of motion in the hip and shoulder joints: passive of 15-20%, and active of 10-30%, muscle strength of 10-30%, improvement of motor activity indices (scale of Bobaht and quality of life (scale of Barthel.

  1. Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice.

    Science.gov (United States)

    Kosuge, Yasuhiro; Miyagishi, Hiroko; Yoneoka, Yuki; Yoneda, Keiko; Nango, Hiroshi; Ishige, Kumiko; Ito, Yoshihisa

    2017-07-04

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice. Copyright © 2017 Elsevier Ltd. All rights

  2. Combined rTMS and virtual reality brain-computer interface training for motor recovery after stroke

    Science.gov (United States)

    Johnson, N. N.; Carey, J.; Edelman, B. J.; Doud, A.; Grande, A.; Lakshminarayan, K.; He, B.

    2018-02-01

    Objective. Combining repetitive transcranial magnetic stimulation (rTMS) with brain-computer interface (BCI) training can address motor impairment after stroke by down-regulating exaggerated inhibition from the contralesional hemisphere and encouraging ipsilesional activation. The objective was to evaluate the efficacy of combined rTMS  +  BCI, compared to sham rTMS  +  BCI, on motor recovery after stroke in subjects with lasting motor paresis. Approach. Three stroke subjects approximately one year post-stroke participated in three weeks of combined rTMS (real or sham) and BCI, followed by three weeks of BCI alone. Behavioral and electrophysiological differences were evaluated at baseline, after three weeks, and after six weeks of treatment. Main results. Motor improvements were observed in both real rTMS  +  BCI and sham groups, but only the former showed significant alterations in inter-hemispheric inhibition in the desired direction and increased relative ipsilesional cortical activation from fMRI. In addition, significant improvements in BCI performance over time and adequate control of the virtual reality BCI paradigm were observed only in the former group. Significance. When combined, the results highlight the feasibility and efficacy of combined rTMS  +  BCI for motor recovery, demonstrated by increased ipsilesional motor activity and improvements in behavioral function for the real rTMS  +  BCI condition in particular. Our findings also demonstrate the utility of BCI training alone, as shown by behavioral improvements for the sham rTMS  +  BCI condition. This study is the first to evaluate combined rTMS and BCI training for motor rehabilitation and provides a foundation for continued work to evaluate the potential of both rTMS and virtual reality BCI training for motor recovery after stroke.

  3. Relationship between functional connectivity and motor function assessment in stroke patients with hemiplegia: a resting-state functional MRI study

    International Nuclear Information System (INIS)

    Zhang, Ye; Wang, Li; Zhang, Jingna; Sang, Linqiong; Li, Pengyue; Qiu, Mingguo; Liu, Hongliang; Yan, Rubing; Yang, Jun; Wang, Jian

    2016-01-01

    Resting-state functional magnetic resonance imaging (fMRI) has been used to examine the brain mechanisms of stroke patients with hemiplegia, but the relationship between functional connectivity (FC) and treatment-induced motor function recovery has not yet been fully investigated. This study aimed to identify the brain FC changes in stroke patients and study the relationship between FC and motor function assessment using the resting-state fMRI. Seventeen stroke patients with hemiplegia and fifteen healthy control subjects (HCSs) were recruited in this study. We compared the FC between the ipsilesional primary motor cortex (M1) and the whole brain of the patients with the FC of the HCSs and studied the FC changes in the patients before and after conventional rehabilitation and motor imagery therapy. Additionally, correlations between the FC change and motor function of the patients were studied. Compared to the HCSs, the FC in the patient group was significantly increased between the ipsilesional M1 and the ipsilesional inferior parietal cortex, frontal gyrus, supplementary motor area (SMA), and contralesional angular and decreased between the ipsilesional M1 and bilateral M1. After the treatment, the FC between the ipsilesional M1 and contralesional M1 increased while the FC between the ipsilesional M1 and ipsilesional SMA and paracentral lobule decreased. A statistically significant correlation was found between the FC change in the bilateral M1 and the Fugl-Meyer assessment (FMA) score change. Our results revealed an abnormal motor network after stroke and suggested that the FC could serve as a biomarker of motor function recovery in stroke patients with hemiplegia. (orig.)

  4. Combined rTMS and virtual reality brain-computer interface training for motor recovery after stroke.

    Science.gov (United States)

    Johnson, N N; Carey, J; Edelman, B J; Doud, A; Grande, A; Lakshminarayan, K; He, B

    2018-02-01

    Combining repetitive transcranial magnetic stimulation (rTMS) with brain-computer interface (BCI) training can address motor impairment after stroke by down-regulating exaggerated inhibition from the contralesional hemisphere and encouraging ipsilesional activation. The objective was to evaluate the efficacy of combined rTMS  +  BCI, compared to sham rTMS  +  BCI, on motor recovery after stroke in subjects with lasting motor paresis. Three stroke subjects approximately one year post-stroke participated in three weeks of combined rTMS (real or sham) and BCI, followed by three weeks of BCI alone. Behavioral and electrophysiological differences were evaluated at baseline, after three weeks, and after six weeks of treatment. Motor improvements were observed in both real rTMS  +  BCI and sham groups, but only the former showed significant alterations in inter-hemispheric inhibition in the desired direction and increased relative ipsilesional cortical activation from fMRI. In addition, significant improvements in BCI performance over time and adequate control of the virtual reality BCI paradigm were observed only in the former group. When combined, the results highlight the feasibility and efficacy of combined rTMS  +  BCI for motor recovery, demonstrated by increased ipsilesional motor activity and improvements in behavioral function for the real rTMS  +  BCI condition in particular. Our findings also demonstrate the utility of BCI training alone, as shown by behavioral improvements for the sham rTMS  +  BCI condition. This study is the first to evaluate combined rTMS and BCI training for motor rehabilitation and provides a foundation for continued work to evaluate the potential of both rTMS and virtual reality BCI training for motor recovery after stroke.

  5. In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons, and enhances SMN2 gene expression in severe spinal muscular atrophy mice.

    Science.gov (United States)

    Biondi, Olivier; Branchu, Julien; Sanchez, Gabriel; Lancelin, Camille; Deforges, Séverine; Lopes, Philippe; Pariset, Claude; Lécolle, Sylvie; Côté, Jocelyn; Chanoine, Christophe; Charbonnier, Frédéric

    2010-08-25

    Spinal muscular atrophy (SMA), a lethal neurodegenerative disease that occurs in childhood, is caused by the misexpression of the survival of motor neuron (SMN) protein in motor neurons. It is still unclear whether activating motor units in SMA corrects the delay in the postnatal maturation of the motor unit resulting in an enhanced neuroprotection. In the present work, we demonstrate that an adequate NMDA receptor activation in a type 2 SMA mouse model significantly accelerated motor unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase of SMN expression resulting from a modification of SMN2 gene transcription pattern. These beneficial effects were dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. In addition, these results suggest that the NMDA-induced acceleration of motor unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different mouse models of severe SMA. The analysis of the intracellular signaling cascade that lay downstream the activated NMDA receptor revealed an unexpected reactivation of the CaMKII/AKT/CREB (cAMP response element-binding protein) pathway that induced an enhanced SMN expression. Therefore, pharmacological activation of spinal NMDA receptors could constitute a useful strategy for both increasing SMN expression and limiting motor neuron death in SMA spinal cord.

  6. Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease.

    Science.gov (United States)

    Lim, M A; Selak, M A; Xiang, Z; Krainc, D; Neve, R L; Kraemer, B C; Watts, J L; Kalb, R G

    2012-01-18

    A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease.

  7. Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.

    Science.gov (United States)

    Gautam, Mukesh; Jara, Javier H; Sekerkova, Gabriella; Yasvoina, Marina V; Martina, Marco; Özdinler, P Hande

    2016-03-15

    Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated Alsin(KO)-UeGFP mice, by crossing Alsin(KO) and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability. © The Author 2016. Published by Oxford University Press.

  8. Optically-Induced Neuronal Activity Is Sufficient to Promote Functional Motor Axon Regeneration In Vivo.

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    Patricia J Ward

    Full Text Available Peripheral nerve injuries are common, and functional recovery is very poor. Beyond surgical repair of the nerve, there are currently no treatment options for these patients. In experimental models of nerve injury, interventions (such as exercise and electrical stimulation that increase neuronal activity of the injured neurons effectively enhance axon regeneration. Here, we utilized optogenetics to determine whether increased activity alone is sufficient to promote motor axon regeneration. In thy-1-ChR2/YFP transgenic mice in which a subset of motoneurons express the light-sensitive cation channel, channelrhodopsin (ChR2, we activated axons in the sciatic nerve using blue light immediately prior to transection and surgical repair of the sciatic nerve. At four weeks post-injury, direct muscle EMG responses evoked with both optical and electrical stimuli as well as the ratio of these optical/electrical evoked EMG responses were significantly greater in mice that received optical treatment. Thus, significantly more ChR2+ axons successfully re-innervated the gastrocnemius muscle in mice that received optical treatment. Sections of the gastrocnemius muscles were reacted with antibodies to Synaptic Vesicle Protein 2 (SV2 to quantify the number of re-occupied motor endplates. The number of SV2+ endplates was greater in mice that received optical treatment. The number of retrogradely-labeled motoneurons following intramuscular injection of cholera toxin subunit B (conjugated to Alexa Fluor 555 was greater in mice that received optical treatment. Thus, the acute (1 hour, one-time optical treatment resulted in robust, long-lasting effects compared to untreated animals as well as untreated axons (ChR2-. We conclude that neuronal activation is sufficient to promote motor axon regeneration, and this regenerative effect is specific to the activated neurons.

  9. Diagnostic accuracy of electrically elicited multiplet discharges in patients with motor neuron disease.

    Science.gov (United States)

    Sleutjes, Boudewijn T H M; Montfoort, Inger; van Doorn, Pieter A; Visser, Gerhard H; Blok, Joleen H

    2015-11-01

    To determine and compare the diagnostic accuracy of electrically elicited multiplet discharges (MDs) and fasciculation potentials (FPs) in motor neuron disease (MND). Patients were eligible when they had MND in their differential diagnosis and were referred for electromyogram (EMG). Stimulated high-density surface EMG of the thenar muscles was performed on the same day as standard EMG examination. High-density recordings were analysed for presence of MDs and needle EMG of any muscle investigated in the cervical region for presence of FPs. Of the 61 patients enrolled in this diagnostic study, 24 patients were clinically diagnosed with amyotrophic lateral sclerosis (ALS) and 11 patients with progressive muscular atrophy (PMA). Another diagnosis was made in 26 patients. Sixteen patients in whom MDs were detected were diagnosed with either ALS (n = 11) or PMA (n = 5; sensitivity = 47.1%, PPV = 94.1%). MDs were detected in only one patient initially diagnosed with PMA, but in whom later on, multifocal motor neuropathy could not be excluded (specificity = 96.2%). Electrically elicited MDs had a higher specificity than FPs (96.2% vs 53.9%, p motor neuron involvement of ≥ 1 EMG region increased from 50% to 73.5% (p = 0.008, n = 34). Electrically evoked MDs are highly specific for ALS and PMA and are an early sign of lower motor neuron dysfunction. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  10. Developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1α.

    Directory of Open Access Journals (Sweden)

    Elizabeth K Lucas

    Full Text Available Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α in the pathophysiology of Huntington Disease (HD. Adult PGC-1α (-/- mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1α have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1α alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1α (-/- mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1α (-/- mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1α (-/- mice can be completely recapitulated by conditional nervous system deletion of PGC-1α, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1α (-/- striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1α deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1α (-/- mice show increases in the expression of medium spiny neuron (MSN markers with age, suggesting that the observed behavioral and structural abnormalities are not primarily due to MSN loss, the defining pathological feature of HD. These results indicate that PGC-1α is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1α leads to long-term alterations in motor functioning.

  11. Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties.

    Science.gov (United States)

    Saporta, Mario A; Dang, Vu; Volfson, Dmitri; Zou, Bende; Xie, Xinmin Simon; Adebola, Adijat; Liem, Ronald K; Shy, Michael; Dimos, John T

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies associated with mutations or copy number variations in over 70 genes encoding proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Here, we used iPSC-derived cells to identify common pathophysiological mechanisms in axonal CMT. iPSC lines from patients with two distinct forms of axonal CMT (CMT2A and CMT2E) were differentiated into spinal cord motor neurons and used to study axonal structure and function and electrophysiological properties in vitro. iPSC-derived motor neurons exhibited gene and protein expression, ultrastructural and electrophysiological features of mature primary spinal cord motor neurons. Cytoskeletal abnormalities were found in neurons from a CMT2E (NEFL) patient and corroborated by a mouse model of the same NEFL point mutation. Abnormalities in mitochondrial trafficking were found in neurons derived from this patient, but were only mildly present in neurons from a CMT2A (MFN2) patient. Novel electrophysiological abnormalities, including reduced action potential threshold and abnormal channel current properties were observed in motor neurons derived from both of these patients. Human iPSC-derived motor neurons from axonal CMT patients replicated key pathophysiological features observed in other models of MFN2 and NEFL mutations, including abnormal cytoskeletal and mitochondrial dynamics. Electrophysiological abnormalities found in axonal CMT iPSC-derived human motor neurons suggest that these cells are hyperexcitable and have altered sodium and calcium channel kinetics. These findings may provide a new therapeutic target for this group of heterogeneous inherited neuropathies. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Reappraisal of VAChT-Cre: Preference in slow motor neurons innervating type I or IIa muscle fibers.

    Science.gov (United States)

    Misawa, Hidemi; Inomata, Daijiro; Kikuchi, Miseri; Maruyama, Sae; Moriwaki, Yasuhiro; Okuda, Takashi; Nukina, Nobuyuki; Yamanaka, Tomoyuki

    2016-11-01

    VAChT-Cre.Fast and VAChT-Cre.Slow mice selectively express Cre recombinase in approximately one half of postnatal somatic motor neurons. The mouse lines have been used in various studies with selective genetic modifications in adult motor neurons. In the present study, we crossed VAChT-Cre lines with a reporter line, CAG-Syp/tdTomato, in which synaptophysin-tdTomato fusion proteins are efficiently sorted to axon terminals, making it possible to label both cell bodies and axon terminals of motor neurons. In the mice, Syp/tdTomato fluorescence preferentially co-localized with osteopontin, a recently discovered motor neuron marker for slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) types. The fluorescence did not preferentially co-localize with matrix metalloproteinase-9, a marker for fast-twitch fatigable (FF) motor neurons. In the neuromuscular junctions, Syp/tdTomato fluorescence was detected mainly in motor nerve terminals that innervate type I or IIa muscle fibers. These results suggest that the VAChT-Cre lines are Cre-drivers that have selectivity in S and FR motor neurons. In order to avoid confusion, we have changed the mouse line names from VAChT-Cre.Fast and VAChT-Cre.Slow to VAChT-Cre.Early and VAChT-Cre.Late, respectively. The mouse lines will be useful tools to study slow-type motor neurons, in relation to physiology and pathology. © 2016 Wiley Periodicals, Inc.

  13. Decoding Upper Limb Movement Attempt From EEG Measurements of the Contralesional Motor Cortex in Chronic Stroke Patients.

    Science.gov (United States)

    Antelis, Javier M; Montesano, Luis; Ramos-Murguialday, Ander; Birbaumer, Niels; Minguez, Javier

    2017-01-01

    Stroke survivors usually require motor rehabilitation therapy as, due to the lesion, they completely or partially loss mobility in the limbs. Brain-computer interface technology offers the possibility of decoding the attempt to move paretic limbs in real time to improve existing motor rehabilitation. However, a major difficulty for the practical application of the BCI to stroke survivors is that the brain rhythms that encode the motor states might be diminished due to the lesion. This study investigates the continuous decoding of natural attempt to move the paralyzed upper limb in stroke survivors from electroencephalographic signals of the unaffected contralesional motor cortex. Experiments were carried out with the aid of six severely affected chronic stroke patients performing/attempting self-selected reaching movements of the unaffected/affected upper limb. The electroencephalographic (EEG) analysis showed significant cortical activation on the uninjured motor cortex when moving the contralateral unaffected arm and in the attempt to move the ipsilateral affected arm. Using this activity, significant continuous decoding of movement was obtained in six out of six participants in movements of the unaffected limb, and in four out of six participants in the attempt to move the affected limb. This study showed that it is possible to construct a decoder of the attempt to move the paretic arm for chronic stroke patients using the EEG activity of the healthy contralesional motor cortex. This decoding model could provide to stroke survivors with a natural, easy, and intuitive way to achieve control of BCIs or robot-assisted rehabilitation devices.

  14. Structural and functional brain signatures of C9orf72 in motor neuron disease.

    Science.gov (United States)

    Agosta, Federica; Ferraro, Pilar M; Riva, Nilo; Spinelli, Edoardo Gioele; Domi, Teuta; Carrera, Paola; Copetti, Massimiliano; Falzone, Yuri; Ferrari, Maurizio; Lunetta, Christian; Comi, Giancarlo; Falini, Andrea; Quattrini, Angelo; Filippi, Massimo

    2017-09-01

    This study investigated structural and functional magnetic resonance imaging abnormalities in hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) motor neuron disease (MND) relative to disease severity-matched sporadic MND cases. We enrolled 19 C9orf72 and 67 disease severity-matched sporadic MND patients, and 22 controls. Sporadic cases were grouped in patients with: no cognitive/behavioral deficits (sporadic-motor); same patterns of cognitive/behavioral impairment as C9orf72 cases (sporadic-cognitive); shorter disease duration versus other sporadic groups (sporadic-early). C9orf72 patients showed cerebellar and thalamic atrophy versus all sporadic cases. All MND patients showed motor, frontal, and temporoparietal cortical thinning and motor and extramotor white matter damage versus controls, independent of genotype and presence of cognitive impairment. Compared with sporadic-early, C9orf72 patients revealed an occipital cortical thinning. C9orf72 patients had enhanced visual network functional connectivity versus sporadic-motor and sporadic-early cases. Structural cerebellar and thalamic damage and posterior cortical alterations are the brain magnetic resonance imaging signatures of C9orf72 MND. Frontotemporal cortical and widespread white matter involvement are likely to be an effect of the disease evolution rather than a C9orf72 marker. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. An investigation into the inter-relationships of sulphur xeno-biotransformation pathways in Parkinson's and motor neurone diseases.

    Science.gov (United States)

    Steventon, Glyn B; Waring, Rosemary H; Williams, Adrian C

    2003-01-01

    The role of defective 'sulphur xenobiotic' biotransformations in the aetiology of Parkinson's and motor neurone diseases has been in the literature for over a decade. Problems in the S-oxidation of aliphatic thioethers, sulphation of phenolic compounds and the S-methylation of aliphatic sulphydryl groups have all been reported. These reports have also been consistent in observing that only a 'significant minority' of patients express these problems in sulphur biotransformation pathways. However, no investigation has yet reported on the incidence of these three defective pathways in control invididuals and in patients with Parkinson's and motor neurone disease. This investigation has found that: 1. Forty percent of patients with Parkinson's and motor neurone disease have a defect in the S-oxidation of S-carboxymethyl-L-cysteine compared to 4% of controls. 2. 35-40% of patients with Parkinson's and motor neurone disease have a defect in the sulphation of paracetamol compared to 4% of controls. 3. 60% of patients with motor neurone disease have a high capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 4. 38% of patients with Parkinson's disease have a low capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 5. There is no correlation between the S-oxidation phenotype, low paracetamol sulphation phenotype and low or high S-methylation phenotype in controls or patients with Parkinson's or motor neurone disease. 6. The number of controls that expressed one of the aberrant phenotypes was 4% compared to 38% of the patients with Parkinson's disease and 47% of the patients with motor neurone disease. 7. The number of controls that expressed two of the aberrant phenotypes was 0% compared to 18% of the patients with Parkinson's disease and 19% of those with motor neurone disease. 8. No controls or patients with Parkinson's disease or motor neurone disease expressed all three of the aberrant phenotypes. The results

  16. Motor Cortex and Motor Cortical Interhemispheric Communication in Walking After Stroke: The Roles of Transcranial Magnetic Stimulation and Animal Models in Our Current and Future Understanding.

    Science.gov (United States)

    Charalambous, Charalambos C; Bowden, Mark G; Adkins, DeAnna L

    2016-01-01

    Despite the plethora of human neurophysiological research, the bilateral involvement of the leg motor cortical areas and their interhemispheric interaction during both normal and impaired human walking is poorly understood. Using transcranial magnetic stimulation (TMS), we have expanded our understanding of the role upper-extremity motor cortical areas play in normal movements and how stroke alters this role, and probed the efficacy of interventions to improve post-stroke arm function. However, similar investigations of the legs have lagged behind, in part, due to the anatomical difficulty in using TMS to stimulate the leg motor cortical areas. Additionally, leg movements are predominately bilaterally controlled and require interlimb coordination that may involve both hemispheres. The sensitive, but invasive, tools used in animal models of locomotion hold great potential for increasing our understanding of the bihemispheric motor cortical control of walking. In this review, we discuss 3 themes assoc